Compounds and methods for treatment of viral infections

ABSTRACT

Compounds and methods of using said compounds, singly or in combination with additional agents, and salts or pharmaceutical compositions of said compounds for the treatment of viral infections are disclosed.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 18/115,955, filed onMar. 1, 2023, which claims the benefit of U.S. Provisional ApplicationNo. 63/315,769, filed on Mar. 2, 2022, U.S. Provisional Application No.63/390,421, filed on Jul. 19, 2022, U.S. Provisional Application No.63/424,083, filed on Nov. 9, 2022, and U.S. Provisional Application No.63/434,993, filed on Dec. 23, 2022. The entire contents of theseapplications are incorporated herein by reference in their entirety.

BACKGROUND

There is a need for compounds and methods for treating viral infections,for example paramyxoviridae, pneumoviridae, picornaviridae,flaviviridae, filoviridae, arenaviridae, orthomyxovirus, andcoronaviridae infections. The present disclosure addresses these andother needs.

The oral route is a preferred route for daily drug administration, dueto its advantages, such as non-invasiveness, patient compliance, andconvenience of drug administration. Nevertheless, oral administrationcan be limited due to poor physicochemical properties of the drugmolecule, including low aqueous solubility between pH2 and pH7,instability, low permeability, and rapid metabolism, all of which cancombine to result in low and irregular oral bioavailability. Oralbioavailability (F %) is the fraction of an oral administered drug thatreaches systemic circulation relative to the same dose delivery byintravenous administration. After intravenous administration, a drug isdirectly and fully available in the bloodstream and can be distributedvia systemic circulation to the point where a pharmacological effecttakes place. If a drug is administered orally, it has to survive theintestinal fluid, cross further barriers such as the gastero-intestinal(GI) cell layer and then the liver in order to reach the systemiccirculation, which can significantly reduce the amount of administereddrug that reaches the bloodstream. Oral bioavailability is therefore animportant property in drug design and development. A high oralbioavailability reduces the required amount of an administered drug thatwould be necessary to achieve a desired pharmacological effect andtherefore could reduce the risk of side-effects and toxicity during theabsorption process. The present disclosure also provides compounds withcombined solubility, stability and permeability properties leading toimproved oral bioavailabilty.

SUMMARY

The instant disclosure provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, andBase are defined herein.

Also provided herein is a pharmaceutical composition comprising acompound disclosed herein (e.g., a compound of Formula I), or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.

Also provided herein is a method of treating or preventing a viralinfection in a human in need thereof, wherein the method comprisesadministering to the human a compound disclosed herein (e.g., a compoundof Formula I), or a pharmaceutically acceptable salt thereof, or apharmaceutical composition described herein.

Also provided herein is a use of a compound disclosed herein (e.g., acompound of Formula I), or a pharmaceutically acceptable salt thereof,for the manufacture of a medicament for the treatment or prevention of aviral infection in a human in need thereof.

Also provided herein is a composition comprising a compound describedherein (e.g., a compound of Formula I), or a pharmaceutically acceptablesalt thereof, for use in treatment or prevention of a viral infection ina human in need thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 : Shows GI stability of Compound 4, Compound 128, Ester ReferenceCompound, and 3^(rd) Ester Reference Compound.

FIG. 2 : Shows the Stability of Compound 128, Compound 129, EsterReference Compound, 2^(nd) Ester Reference Compound, and 3^(rd) EsterReference Compound.

DETAILED DESCRIPTION OF THE INVENTION I. General

The invention relates generally to methods and compounds for treating orpreventing viral infections, for example paramyxoviridae, pneumoviridae,picornaviridae, flaviviridae, filoviridae, arenaviridae, orthomyxovirus,and coronaviridae infections.

II. Definitions

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C₁-C₂₀alkyl), 1 to 8 carbon atoms (i.e., C₁-C₈ alkyl), 1 to 6 carbon atoms(i.e., C₁-C₆ alkyl), or 1 to 3 carbon atoms (i.e., C₁-C₃ alkyl).Examples of suitable alkyl groups include, but are not limited to,methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl,—CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu,n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂), and3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃.

“Alkenyl” refers to an aliphatic group containing at least onecarbon-carbon double bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkenyl), 2 to 8 carbon atoms (i.e., C_(2-s) alkenyl), 2 to 6carbon atoms (i.e., C₂₋₆ alkenyl), or 2 to 4 carbon atoms (i.e., C₂₋₄alkenyl). Examples of alkenyl groups include ethenyl, propenyl,butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an aliphatic group containing at least onecarbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e.,C₂₋₂₀ alkynyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbonatoms (i.e., C₂₋₆ alkynyl), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl).The term “alkynyl” also includes those groups having one triple bond andone double bond.

“Haloalkyl” is an alkyl group, as defined above, in which one or morehydrogen atoms of the alkyl group is replaced with a halogen atom. Thealkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e.,C₁-C₂₀ haloalkyl), 1 to 12 carbon atoms (i.e., C₁-C₁₂ haloalkyl), 1 to 8carbon atoms (i.e., C₁-C₈ haloalkyl), 1 to 6 carbon atoms (i.e., C₁-C₆alkyl) or 1 to 3 carbon atoms (i.e., C₁-C₃ alkyl). Examples of suitablehaloalkyl groups include, but are not limited to, —CF₃, —CHF₂, —CFH₂,—CH₂CF₃, and the like.

“Aryl” means an aromatic hydrocarbon radical derived by the removal ofone hydrogen atom from a single carbon atom of a parent aromatic ringsystem. For example, an aryl group can have 6 to 20 carbon atoms, 6 to14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include,but are not limited to, radicals derived from benzene (e.g., phenyl),substituted benzene, naphthalene, anthracene, biphenyl, and the like.

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings, or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen, and sulfur. As usedherein, heteroaryl includes 1 to 20 ring atoms (i.e., 1 to 20 memberedheteroaryl), 3 to 12 ring atoms (i.e., 3 to 12 membered heteroaryl) or 3to 8 carbon ring atoms (3 to 8 membered heteroaryl) or 5 to 6 ring atoms(5 to 6 membered heteroaryl). Examples of heteroaryl groups includepyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, andpyrazolyl. Heteroaryl does not encompass or overlap with aryl as definedabove.

“Carbocyclyl” or “carbocyclic ring” refers to a non-aromatic hydrocarbonring consisting of carbon and hydrogen atoms, having from three totwenty carbon atoms, in certain embodiments having from three to fifteencarbon atoms, in certain embodiments having from three to ten carbonatoms, from three to eight carbon atoms, from three to seven carbonatoms, or from 3 to 6 carbon atoms and which is saturated or partiallyunsaturated and attached to the rest of the molecule by a single bond.Carbocyclic rings include, for example, cyclopropane, cyclobutane,cyclopentane, cyclopentene, cyclohexane, cyclohexene,1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, andcyclooctane. Carbocyclic rings include cycloalkyl groups.

“Cycloalkyl” refers to a saturated cyclic alkyl group having a singlering or multiple rings including fused, bridged, and spiro ring systems.As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e.,C₃₋₂₀ cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3to 10 ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbonatoms (i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆cycloalkyl). Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

“Heterocycle” or “heterocyclyl” as used herein includes by way ofexample and not limitation those heterocycles described in Paquette, LeoA.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, NewYork, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistryof Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons,New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and28; and J. Am. Chem. Soc. (1960) 82:5566. For example, “heterocycle”includes a “carbocycle” as defined herein, wherein one or more (e.g. 1,2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O,N, or S). As used herein, heterocycle or heterocyclyl has from 3 to 20ring atoms, 3 to 12 ring atoms, 3 to 10 ring atoms, 3 to 8 ring atoms,or 3 to 6 ring atoms. Ring-forming carbon atoms and heteroatoms of aheterocyle group can be optionally oxidized to form an oxo or sulfidogroup or other oxidized linkage (e.g., C(O), S(O), C(S), or S(O)₂,N-oxide etc.) or a nitrogen atom can be quaternized. The terms“heterocycle” or “heterocyclyl” includes saturated rings and partiallyunsaturated rings. Substituted heterocyclyls include, for example,heterocyclic rings substituted with any of the substituents disclosedherein including carbonyl groups. A non-limiting example of a carbonylsubstituted heterocyclyl is:

Example heterocycles include, but are not limited to, tetrahydrofuranylazetidinyl, and 2-oxo-1,3-dioxol-4-yl.

The term “optionally substituted” in reference to a particular moiety ofthe compound described herein such as the compound of Formula I (e.g.,an optionally substituted aryl group) refers to a moiety wherein allsubstituents are hydrogen or wherein one or more of the hydrogens of themoiety may be replaced by the listed substituents.

Unless otherwise specified, the carbon atoms of the compounds of FormulaI are intended to have a valence of four. If in some chemical structurerepresentations, carbon atoms do not have a sufficient number ofvariables attached to produce a valence of four, the remaining carbonsubstituents needed to provide a valence of four should be assumed to behydrogen.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, or inhibiting the progress of the disorder orcondition to which such term applies, or one or more symptoms of suchdisorder or condition. The term “treatment”, as used herein, refers tothe act of treating, as “treating” is defined immediately above.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. The compounds and compositions disclosed herein may, insome embodiments, be administered to a subject (including a human) whois at risk of having the disease or condition. As used herein, the terms“preventing” and “prevention” encompass the administration of acompound, composition, or pharmaceutically acceptable salt according tothe embodiments disclosed herein pre- or post-exposure of the individualto a virus, but before the appearance of symptoms of the viralinfection, and/or prior to the detection of the virus in the blood. Theterms also refer to prevention of the appearance of symptoms of thedisease and/or to prevent the virus from reaching detectible levels inthe blood. The terms include both pre-exposure prophylaxis (PrEP), aswell as post-exposure prophylaxis (PEP) and event driven or “on demand”prophylaxis. The terms also refer to prevention of perinataltransmission of a virus from mother to baby, by administration to themother before giving birth and to the child within the first days oflife. The terms also refer to prevention of transmission of a virusthrough blood transfusion.

The term “therapeutically effective amount”, as used herein, is theamount of a compound described herein (e.g., a compound of Formula I)present in a composition described herein that is needed to provide adesired level of drug in the secretions and tissues of the airways andlungs, or alternatively, in the bloodstream of a subject to be treatedto give an anticipated physiological response or desired biologicaleffect when such a composition is administered by the chosen route ofadministration. The precise amount will depend upon numerous factors,for example the particular compound described herein (e.g., the compoundof Formula I), the specific activity of the composition, the deliverydevice employed, the physical characteristics of the composition, itsintended use, as well as patient considerations such as severity of thedisease state, patient cooperation, etc., and can readily be determinedby one skilled in the art based upon the information provided herein.

III. Compounds

Any reference to the compounds of the invention described herein alsoincludes a reference to a pharmaceutically acceptable salt thereof.Examples of pharmaceutically acceptable salts of the compounds of theinvention include salts derived from an appropriate base, such as analkali metal or an alkaline earth (for example, Na⁺, Li⁺, K⁺, Ca⁺² andMg⁺²), ammonium and NR₄ ⁺ (wherein R is defined herein).Pharmaceutically acceptable salts of a nitrogen atom or an amino groupinclude (a) acid addition salts formed with inorganic acids, forexample, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamicacids, phosphoric acid, nitric acid and the like; (b) salts formed withorganic acids such as, for example, acetic acid, oxalic acid, tartaricacid, succinic acid, maleic acid, fumaric acid, gluconic acid, citricacid, malic acid, ascorbic acid, benzoic acid, isethionic acid,lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamicacid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonicacid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonicacid, malonic acid, sulfosalicylic acid, glycolic acid,2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalicacid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine,glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucineand the like; and (c) salts formed from elemental anions for example,chlorine, bromine, and iodine. Pharmaceutically acceptable salts of acompound of a hydroxy group include the anion of said compound incombination with a suitable cation such as Na⁺ and NR₄ ⁺.

In some embodiments, R is H, (C₁-C₈) alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, C₆-C₂₀ aryl, or C₂-C₂₀ heterocyclyl.

For therapeutic use, salts of active ingredients of the compounds of theinvention will be pharmaceutically acceptable, i.e., they will be saltsderived from a pharmaceutically acceptable acid or base. However, saltsof acids or bases which are not pharmaceutically acceptable may alsofind use, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whether or not derivedform a pharmaceutically acceptable acid or base, are within the scope ofthe present invention.

It is also to be understood that the compositions herein comprisecompounds of the invention in their un-ionized, as well as zwitterionicform, and combinations with stoichiometric amounts of water as inhydrates.

It is to be noted that all enantiomers, diastereomers, racemic mixtures,tautomers, polymorphs, and pseudopolymorphs of compounds describedherein (e.g., compounds within the scope of Formula I) andpharmaceutically acceptable salts thereof are embraced by the presentinvention. All mixtures of such enantiomers and diastereomers are withinthe scope of the present invention.

The compounds of the invention, exemplified by Formula I may have chiralcenters, e.g., chiral carbon or phosphorus atoms. The compounds of theinvention thus include racemic mixtures of all stereoisomers, includingenantiomers, diastereomers, and atropisomers. In addition, the compoundsof the invention include enriched or resolved optical isomers at any orall asymmetric, chiral atoms. In other words, the chiral centersapparent from the depictions are provided as the chiral isomers orracemic mixtures. Both racemic and diastereomeric mixtures, as well asthe individual optical isomers isolated or synthesized, substantiallyfree of their enantiomeric or diastereomeric partners, are all withinthe scope of the invention. The racemic mixtures are separated intotheir individual, substantially optically pure isomers throughappropriate techniques such as, for example, the separation ofdiastereomeric salts formed with optically active adjuncts, e.g., acidsor bases followed by conversion back to the optically active substances.In most instances, the desired optical isomer is synthesized by means ofstereospecific reactions, beginning with the appropriate stereoisomer ofthe desired starting material.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and 1, D and L, or (+) and (−) areemployed to designate the sign of rotation of plane-polarized light bythe compound, with S, (−), or 1 meaning that the compound islevorotatory while a compound prefixed with R, (+), or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

The compounds of the invention may also exist as tautomeric isomers incertain cases. Although only one delocalized resonance structure may bedepicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.

Any formula or structure given herein, including Formula I compounds, isalso intended to represent unlabeled forms as well as isotopicallylabeled forms of the compounds. Isotopically labeled compounds havestructures depicted by the formulas given herein except that one or moreatoms are replaced by an atom having a selected atomic mass or massnumber. Examples of isotopes that can be incorporated into compounds ofthe disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as, but not limited to ²H(deuterium, D), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S,³⁶Cl and ¹²⁵I. Various isotopically labeled compounds of the presentdisclosure, for example those into which radioactive isotopes such as³H, ¹³C and ¹⁴C are incorporated. Such isotopically labelled compoundsmay be useful in metabolic studies, reaction kinetic studies, detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays or in radioactive treatment ofpatients.

The disclosure also includes compounds (e.g., compounds of Formula I) inwhich from 1 to x hydrogens attached to a carbon atom is/are replaced bydeuterium, in which x is the number of hydrogens in the molecule. Suchcompounds exhibit increased resistance to metabolism and are thus usefulfor increasing the half-life of any compound described herein (e.g.,compounds of Formula I) when administered to a mammal, particularly ahuman. See, for example, Foster, “Deuterium Isotope Effects in Studiesof Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984). Inview of the present disclosure, such compounds are synthesized by meansknown in the art, for example by employing starting materials in whichone or more hydrogens have been replaced by deuterium.

Deuterium labeled or substituted therapeutic compounds of the disclosuremay have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies. Isotopically labeled compounds of thisdisclosure and prodrugs thereof can generally be prepared by carryingout the procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. Itis understood that deuterium in this context is regarded as asubstituent in the compound of Formula I.

In some embodiments, the carbon bonded to the 5 position on thetetrahydrofuranyl ring of Formula I is substituted with one or twodeuterium atoms. In some embodiments, the compound of Formula I is

In some embodiments, the compound of Formula I is

In some embodiments, a carbon of the Base of Formula I is substitutedwith one or more deuterium atoms. In some embodiments, Base is

In some embodiments, a carbon on R¹² of the Base of Formula I issubstituted with one or more deuterium atoms. In some embodiments, acarbon on R¹¹ of the Base of Formula I is substituted with one or moredeuterium atoms. In some embodiments, a carbon on R¹ of Formula I issubstituted with one or more deuterium atoms. In some embodiments, acarbon on R² of Formula I is substituted with one or more deuteriumatoms. In some embodiments, a carbon on R³ of Formula I is substitutedwith one or more deuterium atoms.

In some embodiments, the compound of Formula I is

In some embodiments, Base is

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

Whenever a compound described herein is substituted with more than oneof the same designated group, e.g., “R” or “R”, then it will beunderstood that the groups may be the same or different, i.e., eachgroup is independently selected.

Wavy lines,

, indicate the site of covalent bond attachments to the adjoiningsubstructures, groups, moieties, or atoms.

IV. Compounds

In certain embodiments, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —OH, —OC(═O)R⁴, —OC(═O)OR⁴, or —OP(═O)(OH)(OR⁴);

R² is —OH, —OC(═O)R⁵, —OC(═O)OR⁵, or —OP(═O)(OH)(OR⁵); or

R¹ and R² are taken together to form —OC(═O)O—, —OP(═O)(OH)O—, or—OCR⁶O—;

R³ is —C(═O)OR⁷;

R⁴, R⁵, and R⁷ are each independently C₁-C₂₀ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₁₀ carbocyclyl, C₆-C₁₀ aryl, 4 to 8 membered heterocyclylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N,O, and S;

wherein C₁-C₂₀ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₀ carbocyclyl,C₆-C₁₀ aryl, 4 to 8 membered heterocyclyl, or 5 to 6 membered heteroarylof R⁴, R⁵, and R⁷ are each, independently, optionally substituted withone, two, or three substituents independently selected from the groupconsisting of C₁-C₈ alkyl, halogen, cyano, carbonyl, —N₃, —OR⁸, —NR⁹R¹⁰,—OP(═O)(OH)₂, —OP(═O)(OR⁸)₂, C₃-C₈ carbocyclyl, 4 to 6 memberedheterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, andS, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S, and phenyl;

wherein substituent C₃-C₈ carbocyclyl of R⁴, R⁵, and R⁷ is optionallysubstituted with one, two, or three substituents independently selectedfrom C₁-C₈ alkyl, halogen, —CF₃, cyano, —CH₂CN, and phenyl,

wherein substituent 4 to 6 membered heterocyclyl of R⁴, R⁵, and R⁷ isoptionally substituted with one, two, or three substituentsindependently selected from carbonyl and C₁-C₆ alkyl, and

wherein substituent phenyl of R⁴, R⁵, and R⁷ is optionally substitutedwith one, two or three substituents independently selected from halo,cyano, C₁-C₆ alkyl, and —OR⁸;

R⁶ is H, C₁-C₆ alkyl, C₁-C₆ alkoxy, 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, or C₆-C₁₀aryl;

wherein 5 to 6 membered heteroaryl and C₆-C₁₀ aryl of R⁶ are each,independently, optionally substituted with one, two, or threesubstituents independently selected from halo, cyano, C₁-C₆ alkoxy, andC₁-C₆ alkyl;

each R⁸ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, and 4 to 6 membered heterocyclyl;

wherein C₁-C₆ alkyl of R¹ is optionally substituted with C₃-C₆cycloalkyl or 4 to 6 membered heterocyclyl;

each R⁹ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl;

Base is

R¹¹ is C₁-C₆ alkyl optionally substituted with —OP(═O)(OH)(OR¹⁴);

R¹² is H, C₁-C₆ alkyl, —C(═O)R¹³, or —C(═O)OR¹³;

each R¹³ is independently H or C₁-C₈ alkyl; wherein C₁-C₈ alkyl of R¹³is optionally substituted with one, two, or three substituentsindependently selected from halogen, cyano, —OP(═O)(OH)(OR¹⁴), andphenyl, wherein substituent phenyl of R¹³ is optionally substituted with—OP(═O)(OH)(OR¹⁴); and

each R¹⁴ is independently H, C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀aryl, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatomsselected from N, O, and S; wherein C₁-C₈ alkyl of R¹⁴ is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halogen, cyano, and phenyl.

In certain embodiments, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —OH, —OC(═O)R⁴, or —OC(═O)OR⁴;

R² is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or

R¹ and R² are taken together to form —OC(═O)O—, —OP(═O)(OH)O—, or—OCHR⁶O—;

R³ is —C(═O)OR⁷;

R⁴, R⁵, and R⁷ are each independently C₁-C₂₀ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N,O, and S;

-   -   wherein C₁-C₂₀ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈        carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl, or 5 to        6 membered heteroaryl of R⁴, R⁵, and R⁷ are each, independently,        optionally substituted with one, two, or three substituents        independently selected from the group consisting of C₁-C₈ alkyl,        halogen, cyano, carbonyl, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂,        —OP(═O)(OR⁸)₂, C₃-C₈ carbocyclyl, 4 to 6 membered heterocyclyl        containing 1, 2, or 3 heteroatoms selected from N, O, and S, 5        to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms        selected from N, O, and S, and phenyl;        -   wherein substituent C₃-C₈ carbocyclyl of R⁴, R⁵, and R⁷ is            optionally substituted with one, two, or three substituents            independently selected from C₁-C₈ alkyl, halogen, —CF₃,            cyano, —CH₂CN, and phenyl,        -   wherein substituent 4 to 6 membered heterocyclyl of R⁴, R⁵,            and R⁷ is optionally substituted with one, two, or three            substituents independently selected from carbonyl and C₁-C₆            alkyl, and        -   wherein substituent phenyl of R⁴, R⁵, and R⁷ is optionally            substituted with one, two or three substituents            independently selected from halo, cyano, C₁-C₆ alkyl, and            —OR⁸;

R⁶ is H, C₁-C₆ alkyl, C₁-C₆ alkoxy, 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, or C₆-C₁₀aryl;

-   -   wherein 5 to 6 membered heteroaryl and C₆-C₁₀ aryl of R⁶ are        each, independently, optionally substituted with one, two, or        three substituents independently selected from halo, cyano,        C₁-C₆ alkoxy, and C₁-C₆ alkyl;

each R⁸ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl;

each R⁹ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl;

Base is

R¹¹ is C₁-C₆ alkyl optionally substituted with —OP(═O)(OH)(OR¹⁴);

R¹² is H, C₁-C₆ alkyl, —C(═O)R¹³, or —C(═O)OR¹³;

each R¹³ is independently H or C₁-C₈ alkyl; wherein C₁-C₈ alkyl of R¹³is optionally substituted with one, two, or three substituentsindependently selected from halogen, cyano, —OP(═O)(OH)(OR¹⁴), andphenyl, wherein substituent phenyl of R¹³ is optionally substituted with—OP(═O)(OH)(OR¹⁴); and

each R¹⁴ is independently H, C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀aryl, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatomsselected from N, O, and S; wherein C₁-C₈ alkyl of R¹⁴ is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halogen, cyano, and phenyl.

In certain embodiments, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —OH, —OC(═O)R⁴, or —OC(═O)OR⁴;

R² is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or

R¹ and R² are taken together to form —OC(═O)O—, —OP(═O)(OH)O—, or—OCHR⁶O—;

R³ is —C(═O)OR⁷;

R⁴, R⁵, and R⁷ are each independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N,O, and S;

-   -   wherein C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈        carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl, or 5 to        6 membered heteroaryl of R⁴, R⁵, and R⁷ are each, independently,        optionally substituted with one, two, or three substituents        independently selected from the group consisting of C₁-C₈ alkyl,        halogen, cyano, carbonyl, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂,        C₃-C₈ carbocyclyl, 4 to 6 membered heterocyclyl containing 1, 2,        or 3 heteroatoms selected from N, O, and S, 5 to 6 membered        heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O,        and S, and phenyl;        -   wherein substituent 4 to 6 membered heterocyclyl of R⁴, R⁵,            and R⁷ is optionally substituted with one, two, or three            substituents independently selected from carbonyl and C₁-C₆            alkyl, and wherein substituent phenyl of R⁴, R⁵, and R⁷ is            optionally substituted with one, two or three substituents            independently selected from halo, cyano, and C₁-C₆ alkyl;

R⁶ is H, C₁-C₆ alkyl, C₁-C₆ alkoxy, 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, or C₆-C₁₀aryl;

-   -   wherein 5 to 6 membered heteroaryl and C₆-C₁₀ aryl of R⁶ are        each, independently, optionally substituted with one, two, or        three substituents independently selected from halo, cyano,        C₁-C₆ alkoxy, and C₁-C₆ alkyl;

each R⁸ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl;

each R⁹ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl;

Base is

R¹¹ is C₁-C₆ alkyl optionally substituted with —OP(═O)(OH)(OR¹⁴);

R¹² is H, C₁-C₆ alkyl, —C(═O)R¹³ or —C(═O)OR¹³;

each R¹³ is independently H or C₁-C₈ alkyl; wherein C₁-C₈ alkyl of R¹³is optionally substituted with one, two, or three substituentsindependently selected from halogen, cyano, —OP(═O)(OH)(OR¹⁴), andphenyl, wherein substituent phenyl of R¹³ is optionally substituted with—OP(═O)(OH)(OR¹⁴); and

each R¹⁴ is independently H, C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀aryl, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatomsselected from N, O, and S; wherein C₁-C₈ alkyl of R¹⁴ is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halogen, cyano, and phenyl.

In certain embodiments, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is —OH, —OC(═O)R⁴, or —OC(═O)OR⁴;

R² is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or

R¹ and R² are taken together to form —OC(═O)O—, —OP(═O)(OH)O—, or—OCHR⁶O—;

R³ is —C(═O)OR⁷;

R⁴, R⁵, and R⁷ are each independently C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, or 5 to 6membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N,O, and S;

-   -   wherein C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈        carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl, or 5 to        6 membered heteroaryl of R⁴, R⁵, and R⁷ are each, independently,        optionally substituted with one, two, or three substituents        independently selected from the group consisting of halogen,        cyano, carbonyl, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈        carbocyclyl, 4 to 6 membered heterocyclyl containing 1, 2, or 3        heteroatoms selected from N, O, and S, 5 to 6 membered        heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O,        and S, and phenyl;        -   wherein 4 to 6 membered heterocyclyl is optionally            substituted with one, two, or three substituents            independently selected from carbonyl and C₁-C₆ alkyl, and            wherein phenyl is optionally substituted with one, two or            three substituents independently selected from halo, cyano,            and C₁-C₆ alkyl;

R⁶ is H, C₁-C₆ alkyl, C₁-C₆ alkoxy, 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, or C₆-C₁₀aryl;

-   -   wherein 5 to 6 membered heteroaryl and C₆-C₁₀ aryl are each,        independently, optionally substituted with one, two, or three        substituents independently selected from halo, cyano, C₁-C₆        alkoxy, and C₁-C₆ alkyl;

each R⁸ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl;

each R⁹ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl;

each R¹⁰ is independently H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₃-C₆cycloalkyl;

Base is

R¹¹ is C₁-C₆ alkyl optionally substituted with —OP(═O)(OH)(OR¹⁴);

R¹² is H, C₁-C₆ alkyl, —C(═O)R¹³ or —C(═O)OR¹³; and

each R¹³ is independently H or C₁-C₈ alkyl; wherein C₁-C₈ alkyl of R¹³is optionally substituted with one, two, or three substituentsindependently selected from halogen, cyano, —OP(═O)(OH)(OR¹⁴), andphenyl, wherein phenyl is optionally substituted with —OP(═O)(OH)(OR¹⁴);and

each R¹⁴ is independently H, C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀aryl, or 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatomsselected from N, O, and S; wherein C₁-C₈ alkyl of R¹⁴ is optionallysubstituted with one, two or three substituents independently selectedfrom the group consisting of halogen, cyano, and phenyl.

In some embodiments, R¹ is —OH. In some embodiments, R¹ is —OC(═O)R⁴. Insome embodiments, R¹ is —OC(═O)OR⁴.

In some embodiments, R¹ is —OP(═O)(OH)(OR⁴).

In some embodiments, R² is —OH. In some embodiments, R² is —OC(═O)R⁵. Insome embodiments, R² is —OC(═O)OR⁵.

In some embodiments, R² is —OP(═O)(OH)(OR⁵).

In some embodiments, R¹ and R² are both —OH. In some embodiments, R¹ is—OC(═O)R⁴ and R² is —OC(═O)R⁵. In some embodiments, R¹ is OH, and R² is—OC(═O)R⁵ or —OC(═O)OR⁵. In some embodiments, R¹ is —OC(═O)R⁴ or—OC(═O)OR⁴, and R² is OH. In some embodiments, R¹ and R² are takentogether to form —OC(═O)O— In some embodiments, R¹ and R² are takentogether to form —OP(═O)(OH)O—. In some embodiments, R¹ and R² are takentogether to form —OCHR⁶O—.

In some embodiments, R¹ is OH and R² is —OC(═O)R⁵. In some embodiments,R¹ is OH and R² is OC(═O)OR⁵. In some embodiments, R¹ is —OC(═O)R⁴ andR² is OH. In some embodiments, R¹ is —OC(═O)OR⁴ and R² is OH. In someembodiments, R¹ is —OC(═O)OR⁴ and R² is OC(═O)OR⁵. In some embodiments,R¹ is —OC(═O)R⁴ and R² is OC(═O)OR⁵. In some embodiments, R¹ is—OC(═O)OR⁴ and R² is OC(═O)R⁵.

In some embodiments, R¹ is —OP(═O)(OH)(OR⁴) and R² is —OH.

In some embodiments, R¹ is —OC(═O)CH₃. In some embodiments R² is—OC(═O)CH₃. In some embodiments, R¹ and R² are both —OC(═O)CH₃.

In some embodiments,

R¹ is OH, OC(O)CH(CH₃)₂, or OC(O)CH₃,

R² is OH, OC(O)CH(CH₃)₂, or OC(O)CH₃, or

R¹ and R² are taken together to form —OC(═O)O—.

In some embodiments, R⁴ is C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl;wherein C₁-C₈ alkyl, C₂-C₈ alkenyl, and C₂-C₈ alkynyl of R⁴ are each,independently, optionally substituted with one, two, or threesubstituents independently selected from the group consisting ofhalogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl andphenyl; wherein substituent phenyl of R⁴ is optionally substituted withone, two or three substituents independently selected from halo, cyano,and C₁-C₆ alkyl.

In some embodiments, R⁴ is C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl;wherein C₁-C₈ alkyl, C₂-C₈ alkenyl, and C₂-C₈ alkynyl of R⁴ are each,independently, optionally substituted with one, two, or threesubstituents independently selected from the group consisting ofhalogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl andphenyl; wherein phenyl is optionally substituted with one, two or threesubstituents independently selected from halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁴ is C₁-C₈ alkyl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl. In some embodiments, R⁴ is C₁-C₈ alkyl.

In some embodiments, R⁴ is C₁-C₆ alkyl. In some embodiments, R⁴ is C₁-C₃alkyl. In some embodiments, R⁴ is —CH₃, —CH₂CH₃, —(CH₂)₂CH₃, —CH(CH₃)₂,—(CH₂)₃CH₃, or —C(CH₃)₃. In some embodiments, R⁴ is —CH₃ or —CH(CH₃)₂.

In some embodiments, R⁴ is —CH₃, —CH₂CH₃, —(CH₂)₂CH₃, —CH(CH₃)₂,—(CH₂)₃CH₃, —C(CH₃)₃, or —C(CH₃)₂CH₂CH₃.

In some embodiments, R⁴ is C₁-C₂₀ alkyl substituted with one, two, orthree substituents independently selected from the group consisting ofcarbonyl, —OR⁸, —NR⁹R¹⁰, and —OP(═O)(OH)₂. In some embodiments, R⁴ isC₂-C₈ alkyl substituted with carbonyl and —OR⁸. In some embodiments, R⁴is

In some embodiments, R⁴ is C₂-C₈ alkenyl. In some embodiments, R⁴ is C₄alkenyl. In some embodiments, R⁴ is

In some embodiments, R⁵ is C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl;wherein C₁-C₈ alkyl, C₂-C₈ alkenyl, and C₂-C₈ alkynyl of R⁴ are each,independently, optionally substituted with one, two, or threesubstituents independently selected from the group consisting ofhalogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl andphenyl; wherein substituent phenyl of R⁵ is optionally substituted withone, two or three substituents independently selected from halo, cyano,and C₁-C₆ alkyl.

In some embodiments, R⁵ is C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl;wherein C₁-C₈ alkyl, C₂-C₈ alkenyl, and C₂-C₈ alkynyl of R⁴ are each,independently, optionally substituted with one, two, or threesubstituents independently selected from the group consisting ofhalogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl andphenyl; wherein phenyl is optionally substituted with one, two or threesubstituents independently selected from halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁵ is C₁-C₈ alkyl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl. In some embodiments, R⁵ is C₁-C₈ alkyl.

In some embodiments, R⁵ is C₁-C₆ alkyl. In some embodiments, R⁵ is C₁-C₃alkyl. In some embodiments, R⁵ is —CH₃, —CH₂CH₃, —(CH₂)₂CH₃, —CH(CH₃)₂,—(CH₂)₃CH₃, or —C(CH₃)₃. In some embodiments, R⁵ is —CH₃ or —CH(CH₃)₂.

In some embodiments, R⁵ is —CH₃, —CH₂CH₃, —(CH₂)₂CH₃, —CH(CH₃)₂,—(CH₂)₃CH₃, —C(CH₃)₃, or —C(CH₃)₂CH₂CH₃.

In some embodiments, R⁵ is C₁-C₂₀ alkyl substituted with one, two, orthree substituents independently selected from the group consisting ofcarbonyl, —OR⁸, —NR⁹R¹⁰, and —OP(═O)(OH)₂. In some embodiments, R⁵ isC₂-C₈ alkyl substituted with carbonyl and —OR⁸. In some embodiments, R⁵is

In some embodiments, R⁵ is C₂-C₈ alkenyl. In some embodiments, R⁵ is C₄alkenyl. In some embodiments, R⁵ is

In some embodiments, R⁴ and R⁵ are the same. In some embodiments, R⁴ andR⁵ are different. In some embodiments, R⁴ is C₁-C₈ alkyl and R⁵ is C₁-C₈alkyl. In some embodiments, R⁴ is —CH₃ or —CH(CH₃)₂ and R⁵ is —CH₃ or—CH(CH₃)₂. In some embodiments, R⁴ is —CH₃ and R⁵ is —CH₃. In someembodiments, R⁴ is —CH(CH₃)₂ and R⁵ is —CH(CH₃)₂.

In some embodiments, R⁶ is H. In some embodiments, R⁶ is C₁-C₆ alkyl. Insome embodiments, R⁶ is —CH₃, —CH₂CH₃, —(CH₂)₂CH₃, —CH(CH₃)₂,—(CH₂)₃CH₃, or —C(CH₃)₃. In some embodiments, R⁶ is C₁-C₆ alkoxy. Insome embodiments, R⁶ is —OCH₃.

In some embodiments, R⁶ is 5 to 6 membered heteroaryl containing 1, 2,or 3 heteroatoms selected from N, O, and S optionally substituted withone, two, or three substituents independently selected from halo, cyano,C₁-C₆ alkoxy, and C₁-C₆ alkyl. In some embodiments, R⁶ is 5 to 6membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N,O, and S substituted with one, two, or three substituents independentlyselected from halo, cyano, C₁-C₆ alkoxy, and C₁-C₆ alkyl. In someembodiments, R⁶ is 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S.

In some embodiments, R⁶ is C₆-C₁₀ aryl optionally substituted with one,two, or three substituents independently selected from halo, cyano,C₁-C₆ alkoxy, and C₁-C₆ alkyl. In some embodiments, R⁶ is C₆-C₁₀ arylsubstituted with one, two, or three substituents independently selectedfrom halo, cyano, C₁-C₆ alkoxy, and C₁-C₆ alkyl. In some embodiments, R⁶is C₆-C₁₀ aryl. In some embodiments, R⁶ is phenyl.

In some embodiments, R⁷ is C₁-C₂₀ alkyl, C₂-C₈ alkenyl, C₃-C₁₀carbocyclyl, C₆-C₁₀ aryl, 4 to 8 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from N, O, and S or 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S; whereinC₁-C₂₀ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl, 4 to 6 memberedheterocyclyl, or 5 to 6 membered heteroaryl of R⁷ are each optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of C₁-C₈ alkyl, halogen, cyano, carbonyl, —N₃,—OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, —OP(═O)(OR⁸)₂, C₃-C₈ carbocyclyl, 4 to 6membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N,O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatomsselected from N, O, and S, and phenyl; wherein substituent C₃-C₈carbocyclyl of R⁷ is optionally substituted with one, two, or threesubstituents independently selected from C₁-C₈ alkyl, halogen, —CF₃,cyano, —CH₂CN, and phenyl, wherein substituent 4 to 6 memberedheterocyclyl of R⁷ is optionally substituted with one, two, or threesubstituents independently selected from carbonyl and C₁-C₆ alkyl, andwherein substituent phenyl of R⁷ is optionally substituted with one, twoor three substituents independently selected from halo, cyano, C₁-C₆alkyl, and OR⁸.

In some embodiments, R⁷ is C₁-C₂₀ alkyl, C₂-C₈ alkenyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from N, O, and S or 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S; whereinC₁-C₂₀ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl, 4 to 6 memberedheterocyclyl, or 5 to 6 membered heteroaryl of R⁷ are each optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of C₁-C₈ alkyl, halogen, cyano, carbonyl, —N₃,—OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, —OP(═O)(OR⁸)₂, C₃-C₈ carbocyclyl, 4 to 6membered heterocyclyl containing 1, 2, or 3 heteroatoms selected from N,O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatomsselected from N, O, and S, and phenyl; wherein substituent C₃-C₈carbocyclyl of R⁷ is optionally substituted with one, two, or threesubstituents independently selected from C₁-C₈ alkyl, halogen, —CF₃,cyano, —CH₂CN, and phenyl, wherein substituent 4 to 6 memberedheterocyclyl of R⁷ is optionally substituted with one, two, or threesubstituents independently selected from carbonyl and C₁-C₆ alkyl, andwherein substituent phenyl of R⁷ is optionally substituted with one, twoor three substituents independently selected from halo, cyano, C₁-C₆alkyl, and OR⁸.

In some embodiments, R⁷ is C₁-C₂₀ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₂₀ alkyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl, or 5 to 6membered heteroaryl of R⁷ are each optionally substituted with one, two,or three substituents independently selected from the group consistingof C₁-C₈ alkyl, halogen, cyano, carbonyl, —N₃, —OR⁸, —NR⁹R¹⁰,—OP(═O)(OH)₂, —OP(═O)(OR⁸)₂, C₃-C₈ carbocyclyl, 4 to 6 memberedheterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, andS, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S, and phenyl; wherein substituent C₃-C₈ carbocyclyl ofR⁷ is optionally substituted with one, two, or three substituentsindependently selected from C₁-C₈ alkyl, halogen, —CF₃, cyano, —CH₂CN,and phenyl, wherein substituent 4 to 6 membered heterocyclyl of R⁷ isoptionally substituted with one, two, or three substituentsindependently selected from carbonyl and C₁-C₆ alkyl, and whereinsubstituent phenyl of R⁷ is optionally substituted with one, two orthree substituents independently selected from halo, cyano, C₁-C₆ alkyl,and OR⁸.

In some embodiments, R⁷ is C₁-C₂₀ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₂₀ alkyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl, or 5 to 6membered heteroaryl of R⁷ are each optionally substituted with one, two,or three substituents independently selected from the group consistingof C₁-C₈ alkyl, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, —OP(═O)(OR⁸)₂, C₃-C₈carbocyclyl, 4 to 6 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S, 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl;wherein substituent C₃-C₈ carbocyclyl of R⁷ is optionally substitutedwith one, two, or three substituents independently selected from C₁-C₈alkyl, halogen, —CF₃, cyano, —CH₂CN, and phenyl, wherein substituent 4to 6 membered heterocyclyl of R⁷ is optionally substituted with one,two, or three substituents independently selected from carbonyl andC₁-C₆ alkyl, and wherein substituent phenyl of R⁷ is optionallysubstituted with one, two or three substituents independently selectedfrom halo, cyano, C₁-C₆ alkyl, and OR⁸.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl, and 5 to 6membered heteroaryl of R⁷ are each optionally substituted with one, two,or three substituents independently selected from the group consistingof C₁-C₈ alkyl, —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl, 4 to 6 memberedheterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, andS, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S, and phenyl; wherein substituent 4 to 6 memberedheterocyclyl of R⁷ is optionally substituted with one, two, or threesubstituents independently selected from carbonyl and C₁-C₆ alkyl andwherein substituent phenyl of R⁷ is optionally substituted with one,two, or three substituents independently selected from halo, cyano, andC₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl, and 5 to 6membered heteroaryl of R⁷ are each optionally substituted with one, two,or three substituents independently selected from the group consistingof —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl, 4 to 6 membered heterocyclylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N,O, and S, and phenyl; wherein substituent C₃-C₈ carbocyclyl of R⁷ isoptionally substituted with one, two, or three substituentsindependently selected from C₁-C₈ alkyl, halogen, —CF₃, cyano, —CH₂CN,and phenyl, wherein substituent 4 to 6 membered heterocyclyl of R⁷ isoptionally substituted with one, two, or three substituentsindependently selected from carbonyl and C₁-C₆ alkyl, and whereinsubstituent phenyl of R⁷ is optionally substituted with one, two orthree substituents independently selected from halo, cyano, C₁-C₆ alkyl,and OR⁸.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl, and 5 to 6membered heteroaryl of R⁷ are each optionally substituted with one, two,or three substituents independently selected from the group consistingof —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl, 4 to 6 membered heterocyclylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N,O, and S, and phenyl; wherein substituent 4 to 6 membered heterocyclylof R⁷ is optionally substituted with one, two, or three substituentsindependently selected from carbonyl and C₁-C₆ alkyl and whereinsubstituent phenyl of R⁷ is optionally substituted with one, two, orthree substituents independently selected from halo, cyano, and C₁-C₆alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl, and 5 to 6membered heteroaryl of R⁷ are each optionally substituted with one, two,or three substituents independently selected from the group consistingof —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl, 4 to 6 membered heterocyclylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N,O, and S, and phenyl; wherein 4 to 6 membered heterocyclyl is optionallysubstituted with one, two, or three substituents independently selectedfrom carbonyl and C₁-C₆ alkyl and wherein phenyl is optionallysubstituted with one, two, or three substituents independently selectedfrom halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl, and 5 to 6membered heteroaryl of R⁷ are each optionally substituted with one, two,or three substituents independently selected from the group consistingof C₁-C₈ alkyl, —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl and phenyl;wherein substituent phenyl of R⁷ is optionally substituted with one,two, or three substituents independently selected from halo, cyano, andC₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl, and 5 to 6membered heteroaryl of R⁷ are each optionally substituted with one, two,or three substituents independently selected from the group consistingof —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl and phenyl; wherein substituentphenyl of R⁷ is optionally substituted with one, two, or threesubstituents independently selected from halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl, and 5 to 6membered heteroaryl of R⁷ are each optionally substituted with one, two,or three substituents independently selected from the group consistingof —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl and phenyl; wherein phenyl isoptionally substituted with one, two, or three substituentsindependently selected from halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from N, O, and S, and 5 to 6 memberedheteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and Sof R⁷ are each optionally substituted with one, two, or threesubstituents independently selected from the group consisting of C₁-C₈alkyl, —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl, 4 to 6 memberedheterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, andS, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S, and phenyl; wherein substituent 4 to 6 memberedheterocyclyl of R⁷ is optionally substituted with one, two, or threesubstituents independently selected from carbonyl and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from N, O, and S, and 5 to 6 memberedheteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and Sof R⁷ are each optionally substituted with one, two, or threesubstituents independently selected from the group consisting of —OR⁸,—OP(═O)(OH)₂, C₃-C₈ carbocyclyl, 4 to 6 membered heterocyclyl containing1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 memberedheteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S,and phenyl; wherein substituent 4 to 6 membered heterocyclyl of R⁷ isoptionally substituted with one, two, or three substituentsindependently selected from carbonyl and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from N, O, and S, and 5 to 6 memberedheteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and Sare optionally substituted with one, two, or three substituentsindependently selected from the group consisting of —OR⁸, —OP(═O)(OH)₂,C₃-C₈ carbocyclyl, 4 to 6 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S, 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl;wherein 4 to 6 membered heterocyclyl is optionally substituted with one,two, or three substituents independently selected from carbonyl andC₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from N, O, and S, and 5 to 6 memberedheteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and Sof R⁷ are each optionally substituted with one, two, or threesubstituents independently selected from the group consisting of C₁-C₈alkyl, —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl, 4 to 6 memberedheterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, andS, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S, and phenyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from N, O, and S, and 5 to 6 memberedheteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and Sof R⁷ are each optionally substituted with one, two, or threesubstituents independently selected from the group consisting of —OR⁸,—OP(═O)(OH)₂, C₃-C₈ carbocyclyl, 4 to 6 membered heterocyclyl containing1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 memberedheteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S,and phenyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from N, O, and S, and 5 to 6 memberedheteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and Sare optionally substituted with one, two, or three substituentsindependently selected from the group consisting of —OR⁸, —OP(═O)(OH)₂,C₃-C₈ carbocyclyl, 4 to 6 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S, 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from N, O, and S, and 5 to 6 memberedheteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and Sof R⁷ are each optionally substituted with one, two, or threesubstituents independently selected from the group consisting of C₁-C₈alkyl, —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl and phenyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl, C₃-C₈carbocyclyl, C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from N, O, and S, and 5 to 6 memberedheteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and Sof R⁷ are each optionally substituted with one, two, or threesubstituents independently selected from the group consisting of —OR⁸,—OP(═O)(OH)₂, C₃-C₈ carbocyclyl and phenyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; C₁-C₈ alkyl, C₃-C₈ carbocyclyl,C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S, and 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of —OR⁸, —OP(═O)(OH)₂,C₃-C₈ carbocyclyl and phenyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl of R⁷ isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of C₁-C₈ alkyl, —OR⁸,—OP(═O)(OH)₂, C₃-C₈ carbocyclyl, 4 to 6 membered heterocyclyl containing1, 2, or 3 heteroatoms selected from N, O, and S, 5 to 6 memberedheteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S,and phenyl; wherein substituent 4 to 6 membered heterocyclyl of R⁷ isoptionally substituted with one, two, or three substituentsindependently selected from carbonyl and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl of R⁷ isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of —OR⁸, —OP(═O)(OH)₂,C₃-C₈ carbocyclyl, 4 to 6 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S, 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl;wherein substituent 4 to 6 membered heterocyclyl of R⁷ is optionallysubstituted with one, two, or three substituents independently selectedfrom carbonyl and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl is optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl, 4 to6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected fromN, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S, and phenyl; wherein 4 to 6membered heterocyclyl is optionally substituted with one, two, or threesubstituents independently selected from carbonyl and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl of R⁷ isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of —OR⁸, —OP(═O)(OH)₂,C₃-C₈ carbocyclyl, 4 to 6 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S, 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl is optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl, 4 to6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected fromN, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S, and phenyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl of R⁷ isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of —OR⁸, —OP(═O)(OH)₂,C₃-C₈ carbocyclyl and phenyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl,4 to 6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S; wherein C₁-C₈ alkyl is optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl andphenyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl;wherein C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl of R⁷ are each,independently, optionally substituted with one, two, or threesubstituents independently selected from the group consisting ofhalogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl andphenyl; wherein phenyl is optionally substituted with one, two or threesubstituents independently selected from halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl;wherein C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl are each,independently, optionally substituted with one, two, or threesubstituents independently selected from the group consisting ofhalogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl andphenyl; wherein phenyl is optionally substituted with one, two or threesubstituents independently selected from halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₂₀ alkyl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of C₁-C₈ alkyl, halogen, cyano, carbonyl, —N₃, —OR⁸, —NR⁹R¹⁰,—OP(═O)(OH)₂, —OP(═O)(OR⁸)₂, C₃-C₈ carbocyclyl, 4 to 6 memberedheterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, andS, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S, and phenyl; wherein substituent C₃-C₈ carbocyclyl ofR⁷ is optionally substituted with one, two, or three substituentsindependently selected from C₁-C₈ alkyl, halogen, —CF₃, cyano, —CH₂CN,and phenyl, wherein substituent 4 to 6 membered heterocyclyl of R⁷ isoptionally substituted with one, two, or three substituentsindependently selected from carbonyl and C₁-C₆ alkyl, and whereinsubstituent phenyl of R⁷ is optionally substituted with one, two orthree substituents independently selected from halo, cyano, C₁-C₆ alkyl,and OR⁸.

In some embodiments, R⁷ is C₁-C₂₀ alkyl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl, 4 to 6 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S, 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl;wherein substituent 4 to 6 membered heterocyclyl of R⁷ is optionallysubstituted with one, two, or three substituents independently selectedfrom carbonyl and C₁-C₆ alkyl and wherein substituent phenyl of R⁷ isoptionally substituted with one, two or three substituents independentlyselected from halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl, 4 to 6 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S, 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl;wherein substituent 4 to 6 membered heterocyclyl of R⁷ is optionallysubstituted with one, two, or three substituents independently selectedfrom carbonyl and C₁-C₆ alkyl and wherein substituent phenyl of R⁷ isoptionally substituted with one, two or three substituents independentlyselected from halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl, 4 to 6 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S, 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S, and phenyl;wherein 4 to 6 membered heterocyclyl is optionally substituted with one,two, or three substituents independently selected from carbonyl andC₁-C₆ alkyl and wherein phenyl is optionally substituted with one, twoor three substituents independently selected from halo, cyano, and C₁-C₆alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, carbonyl, —N₃, —OR⁸, —NR⁹R¹⁰,—OP(═O)(OH)₂, C₃-C₈ carbocyclyl and phenyl; wherein substituent C₃-C₈carbocyclyl of R⁷ is optionally substituted with one, two or threesubstituents independently selected from halo, cyano, and C₁-C₆ alkyland wherein substitutent phenyl of R⁷ is optionally substituted withone, two or three substituents independently selected from halo, cyano,and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl; wherein substituent phenyl of R⁷ is optionallysubstituted with one, two or three substituents independently selectedfrom halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl; wherein phenyl is optionally substituted withone, two or three substituents independently selected from halo, cyano,and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₆ alkyl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl; wherein substituent phenyl of R⁷ is optionallysubstituted with one, two or three substituents independently selectedfrom halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₆ alkyl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl; wherein phenyl is optionally substituted withone, two or three substituents independently selected from halo, cyano,and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₁-C₈ alkyl optionally substituted with onesubstituent selected from the group consisting of —OR⁸, —OP(═O)(OH)₂,—OP(═O)(OR⁸)₂, C₃-C₈ carbocyclyl and phenyl.

In some embodiments, R⁷ is C₁-C₈ alkyl optionally substituted with onesubstituent selected from the group consisting of —OR⁸, —OP(═O)(OH)₂,C₃-C₈ carbocyclyl and phenyl. In some embodiments, R⁷ is C₁-C₆ alkyloptionally substituted with one substituent selected from the groupconsisting of —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl and phenyl.

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with halogen. In someembodiments, R⁷ is C₁-C₈ alkyl substituted with —F or —Cl. In someembodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with —OR⁸. In someembodiments, R⁷ is C₂-C₄ alkyl substituted with —OR⁸. In someembodiments, R⁷ is C₂-C₄ alkyl substituted with —OCH₃. In someembodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with —NR⁹R¹⁰. In someembodiments, R⁷ is C₁-C₈ alkyl substituted with —N(CH₃)₂.

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with carbonyl.

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with carbonyl and—OR⁸. In some embodiments, R⁷ is C₁-C₈ alkyl substituted with carbonyland —OCH₂CH₃. In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with carbonyl and—NR⁹R¹⁰. In some embodiments, R⁷ is C₁-C₈ alkyl substituted withcarbonyl and —N(CH₃)₂. In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with carbonyl and—OC(CH₃)₃. In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with carbonyl and—OH. In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with carbonyl,—NR⁹R¹⁰, and —OR⁸. In some embodiments, R⁷ is C₁-C₈ alkyl substitutedwith carbonyl, —N(CH₃)₂, and —OCH₃. In some embodiments, R⁷ is C₁-C₈alkyl substituted with carbonyl, —N(CH₃)₂, and —OCH(CH₃)₂. In someembodiments, R⁷ is C₁-C₈ alkyl substituted with carbonyl, —N(CH₃)₂, and—OCH₂C(CH₃)₃. In some embodiments, R⁷ is C₁-C₈ alkyl substituted withcarbonyl, —N(CH₃)₂, and

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with carbonyl,—N(CH₃)₂, and

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with carbonyl,—N(CH₃)₂, and

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with 5 to 6 memberedheteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S.In some embodiments, R⁷ is alkyl substituted with pyridinyl,pyrimidinyl, or imidazolyl. In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with phenyl whereinsubstituent phenyl of R⁷ is optionally substituted with one, two orthree substituents independently selected from halo, cyano, C₁-C₆ alkyl,and OR⁸. In some embodiments, R⁷ is C₁-C₈ alkyl substituted with phenylwherein substituent phenyl of R⁷ is substituted with OR⁸. In someembodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with phenyl. In someembodiments, R⁷ is C₁-C₄ alkyl substituted with phenyl. In someembodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with C₃-C₈carbocyclyl wherein substituent C₃-C₈ carbocyclyl of R⁷ is optionallysubstituted with one, two, or three substituents independently selectedfrom C₁-C₈ alkyl, halogen, —CF₃, cyano, —CH₂CN, and phenyl. In someembodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with C₃-C₈carbocyclyl. In some embodiments, R⁷ is C₂-C₄ alkyl substituted withC₄-C₇ carbocyclyl. In some embodiments, R⁷ is C₂-C₄ alkyl substitutedwith

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is C₂₋₄ alkyl substituted with

In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with 4 to 6 memberedheterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, andS. In some embodiments, R⁷ is

In some embodiments R⁷ is C₁-C₈ alkyl substituted with 4 to 6 memberedheterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, and Swherein substituent 4 to 6 membered heterocyclyl of R⁷ is substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁-C₈ alkyl and carbonyl. In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with —OP(═O)(OH)₂. Insome embodiments, R⁷ is C₁-C₄ alkyl substituted with —OP(═O)(OH)₂. Insome embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl substituted with —OP(═O)(OR⁸)₂.In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₂₀ alkyl. In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₈ alkyl. In some embodiments, R⁷ is C₁-C₆alkyl. In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₃ alkyl. In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is C₁-C₃ alkyl and R¹ and R² are both—OC(═O)CH₃. In some embodiments, R⁷ is

and R¹ and R² are both —OC(═O)CH₃. In some embodiments, R⁷ is

and R¹ and R² are both —OC(═O)CH₃.

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is C₂-C₈ alkenyl. In some embodiments, R⁷ is

In some embodiments, R⁷ is C₃-C₁₀ carbocyclyl optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁-C₈ alkyl, halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰,—OP(═O)(OH)₂, C₃-C₈ carbocyclyl and phenyl; wherein substituent phenylR⁷ is optionally substituted with one, two or three substituentsindependently selected from halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₃-C₈ carbocyclyl optionally substituted withone, two, or three substituents independently selected from the groupconsisting of C₁-C₈ alkyl, halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰,—OP(═O)(OH)₂, C₃-C₈ carbocyclyl and phenyl; wherein substituent phenylR⁷ is optionally substituted with one, two or three substituentsindependently selected from halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₃-C₈ carbocyclyl optionally substituted withone, two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl; wherein substituent phenyl R⁷ is optionallysubstituted with one, two or three substituents independently selectedfrom halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₃-C₈ carbocyclyl optionally substituted withone, two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl; wherein phenyl is optionally substituted withone, two or three substituents independently selected from halo, cyano,and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₃-C₈ carbocyclyl optionally substituted withone, two, or three substituents independently selected from the groupconsisting of C₁-C₈ alkyl, halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰,—OP(═O)(OH)₂, C₃-C₈ carbocyclyl and phenyl.

In some embodiments, R⁷ is C₃-C₈ carbocyclyl optionally substituted withone, two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl.

In some embodiments, R⁷ is C₃-C₈ carbocyclyl optionally substituted withone, two, or three substituents independently selected from the groupconsisting of C₁-C₈ alkyl, —OR⁸, —NR⁹R¹⁰, C₃-C₈ carbocyclyl and phenyl.

In some embodiments, R⁷ is C₃-C₈ carbocyclyl optionally substituted withone, two, or three substituents independently selected from the groupconsisting of —OR⁸, —NR⁹R¹⁰, C₃-C₈ carbocyclyl and phenyl.

In some embodiments, R⁷ is C₃-C₈ carbocyclyl substituted with one, two,or three substituents independently selected from the group consistingof C₁-C₈ alkyl and halogen. In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is C₃-C₁₀ carbocyclyl. In some embodiments, R⁷is

In some embodiments, R⁷ is C₃-C₈ carbocyclyl. In some embodiments, R⁷is,

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments R⁷ is

In some embodiments, R⁷ is C₆-C₁₀ aryl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of C₁-C₈ alkyl, halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰,—OP(═O)(OH)₂, C₃-C₈ carbocyclyl and phenyl; wherein substituent phenylof R⁷ is optionally substituted with one, two or three substituentsindependently selected from halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₆-C₁₀ aryl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl; wherein substituent phenyl of R⁷ is optionallysubstituted with one, two or three substituents independently selectedfrom halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₆-C₁₀ aryl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl; wherein phenyl is optionally substituted withone, two or three substituents independently selected from halo, cyano,and C₁-C₆ alkyl.

In some embodiments, R⁷ is C₆-C₁₀ aryl optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl.

In some embodiments, R⁷ is phenyl or naphthyl optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂,C₃-C₈ carbocyclyl and phenyl.

In some embodiments, R⁷ is phenyl optionally substituted with one, two,or three substituents independently selected from the group consistingof halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈ carbocyclyland phenyl.

In some embodiments, R⁷ is phenyl substituted with or three substituentsindependently selected from the group consisting of C₁-C₈ alkyl and—OR⁸. In some embodiments,

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is 4 to 8 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from N, O, and S optionally substituted withone, two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl; wherein substituent phenyl of R⁷ is optionallysubstituted with one, two or three substituents independently selectedfrom halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is 4 to 6 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from N, O, and S optionally substituted withone, two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl; wherein substituent phenyl of R⁷ is optionallysubstituted with one, two or three substituents independently selectedfrom halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is 4 to 6 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from N, O, and S optionally substituted withone, two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl; wherein phenyl is optionally substituted withone, two or three substituents independently selected from halo, cyano,and C₁-C₆ alkyl.

In some embodiments, R⁷ is 4 to 6 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from N, O, and S optionally substituted withone, two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl.

In some embodiments, R⁷ is 6 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl.

In some embodiments, R⁷ is

In some embodiments, R⁷ is 5 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl.

In some embodiments, R⁷ is 5 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S. In some embodiments, R⁷ is

In some embodiments, R⁷ is 4 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl.

In some embodiments, R⁷ is 4 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S.

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments, R⁷ is 5 to 6 membered heteroaryl containing 1, 2,or 3 heteroatoms selected from N, O, and S optionally substituted withone, two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl; wherein substituent phenyl of R⁷ is optionallysubstituted with one, two or three substituents independently selectedfrom halo, cyano, and C₁-C₆ alkyl.

In some embodiments, R⁷ is 5 to 6 membered heteroaryl containing 1, 2,or 3 heteroatoms selected from N, O, and S optionally substituted withone, two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl; wherein phenyl is optionally substituted withone, two or three substituents independently selected from halo, cyano,and C₁-C₆ alkyl.

In some embodiments, R⁷ is 5 to 6 membered heteroaryl containing 1, 2,or 3 heteroatoms selected from N, O, and S optionally substituted withone, two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl.

In some embodiments, R⁷ is 5 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl.

In some embodiments, R⁷ is 5 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S.

In some embodiments, R⁷ is 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, —N₃, —OR⁸, —NR⁹R¹⁰, —OP(═O)(OH)₂, C₃-C₈carbocyclyl and phenyl.

In some embodiments, R⁷ is 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S optionally substituted with one,two, or three substituents independently selected from the groupconsisting of halogen, cyano, and —NR⁹R¹⁰.

In some embodiments, R⁷ is 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S. In some embodiments, R⁷ is

In some embodiments, R⁷ is is

In some embodiments, R⁷ is is

In some embodiments, R⁷ is

In some embodiments, R⁷ is

In some embodiments R⁷ is

In some embodiments R⁷ is

In some embodiments, R⁸ is H. In some embodiments, R⁸ is C₁-C₆ alkyl. Insome embodiments, R¹ is —CH₃. In some embodiments, R⁸ is C₁-C₆haloalkyl. In some embodiments, R⁸ is C₃-C₆ cycloalkyl.

In some embodiments, R⁸ is

In some embodiments, R⁸ is —C(CH₃)₃, —CH(CH₃)₂, or —CH₂C(CH₃)₃. In someembodiments, R⁸ is C₁-C₆ alkyl substituted with C₃-C₆ cycloalkyl. Insome embodiments, R⁸ is

In some embodiments, R⁸ is 4 to 6 membered heterocyclyl. In someembodiments, R⁸ is

In some embodiments, R⁹ is H. In some embodiments, R⁹ is C₁-C₆ alkyl. Insome embodiments, R⁹ is —CH₃. In some embodiments, R⁹ is C₁-C₆haloalkyl. In some embodiments, R⁹ is C₃-C₆ cycloalkyl.

In some embodiments, R¹⁰ is H. In some embodiments, R¹⁰ is C₁-C₆ alkyl.In some embodiments, R¹⁰ is —CH₃. In some embodiments, R¹⁰ is C₁-C₆haloalkyl. In some embodiments, R¹⁰ is C₃-C₆ cycloalkyl.

In some embodiments, Base is

In some embodiments, Base is

In some embodiments, Base is

In some embodiments, Base is

In some embodiments, R¹¹ is C₁-C₃ alkyl substituted with—OP(═O)(OH)(OR¹⁴). In some embodiments, R¹¹ is —(CH₂)OP(═O)(OH)(OR¹⁴).

In some embodiments, R¹⁴ is H. In some embodiments, R¹⁴ is H or C₁-C₈alkyl; wherein C₁-C₈ alkyl of R¹⁴ is optionally substituted with one,two or three substituents independently selected from the groupconsisting of halogen, cyano, and phenyl.

In some embodiments, R¹⁴ is C₁-C₈ alkyl optionally substituted with one,two or three substituents independently selected from the groupconsisting of halogen, cyano, and phenyl. In some embodiments, R¹⁴ isC₁-C₃ alkyl optionally substituted with one, two or three substituentsindependently selected from the group consisting of halogen, cyano, andphenyl. In some embodiments, R¹⁴ is C₁-C₃ alkyl substituted with onephenyl. In some embodiments, R¹⁴ is

In some embodiments, R¹¹ is —(CH₂)OP(═O)(OH)₂. In some embodiments, R¹¹is

In some embodiments, R¹² is H. In some embodiments, R¹² is C₁-C₆ alkyl.In some embodiments, R¹² is —C(═O)R¹³. In some embodiments, R¹² is—C(═O)(CH₂)₂CH₃. In some embodiments, R¹² is —C(═O)OR¹³. In someembodiments, R¹² is —C(═O)OCH₂CH(CH₃)₂. In some embodiments, R¹² is—C(═O)OCH₂CH(CH₃)₂ or —C(═O)(CH₂)₂CH₃. In some embodiments, R¹² is

In some embodiments, R¹² is

In some embodiments, R¹² is

In some embodiments, R¹³ is C₁-C₈ alkyl; wherein C₁-C₈ alkyl of R¹³ isoptionally substituted with one, two, or three substituentsindependently selected from halogen, cyano, —OP(═O)(OH)(OR¹⁴) andphenyl, wherein substituent phenyl of R¹³ is optionally substituted with—OP(═O)(OH)(OR¹⁴). In some embodiments, R¹³ is C₁-C₈ alkyl optionallysubstituted with one, two, or three substituents independently selectedfrom halogen, cyano, and phenyl; wherein substituent phenyl of R¹³ isoptionally substituted with —OP(═O)(OH)(OR¹⁴).

In some embodiments, R¹³ is H. In some embodiments, R¹³ is C₁-C₈ alkyl;wherein C₁-C₈ alkyl of R¹³ is optionally substituted with one, two, orthree substituents independently selected from halogen, cyano,—OP(═O)(OH)(OR¹⁴) and phenyl, wherein phenyl is optionally substitutedwith —OP(═O)(OH)(OR¹⁴). In some embodiments, R¹³ is C₁-C₈ alkyloptionally substituted with one, two, or three substituentsindependently selected from halogen, cyano, and phenyl; wherein phenylis optionally substituted with —OP(═O)(OH)(OR¹⁴). In some embodiments,R¹³ is C₁-C₈ alkyl optionally substituted with one, two, or threesubstituents independently selected from halogen, cyano, and phenyl. Insome embodiments, R¹³ is C₁-C₈ alkyl. In some embodiments, R¹³ is —CH₃,—CH₂CH₃, —(CH₂)₂CH₃, —CH(CH₃)₂, —(CH₂)₃CH₃, or —C(CH₃)₃. In someembodiments, R¹³ is —CH₂CH(CH₃)₂ or —(CH₂)₂CH₃. In some embodiments, R¹³is —(CH₂)OP(═O)(OH)₂.

In some embodiments, R¹³ is —(CH₂)CH(CH₃)₂.

In some embodiments, R¹³ is C₁-C₈ alkyl substituted with phenyl. In someembodiments, R¹³ is

In some embodiments, Base is

In some embodiments, Base is

In some embodiments, Base is

In some embodiments

R¹ is —OH or —OC(═O)R⁴;

R² is —OH or —OC(═O)R⁵;

R³ is —C(═O)OR⁷;

R⁴ is C₁-C₃ alkyl;

R⁵ is C₁-C₃ alkyl;

R⁷ is C₁-C₆ alkyl or C₆-C₈ carbocyclyl;

Base is

In some embodiments

R¹ is —OC(═O)R⁴;

R² is —OC(═O)R⁵;

R³ is —C(═O)OR⁷;

R⁴ is C₁-C₃ alkyl;

R⁵ is C₁-C₃ alkyl;

R⁷ is C₁-C₆ alkyl;

Base is

In some embodiments,

R¹ is —OH, —OC(═O)R⁴, —OC(═O)OR⁴, or —OP(═O)(OH)(OR⁴);

R² is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or

R¹ and R² are taken together to form —OC(═O)O—, —OP(═O)(OH)O—, or—OCHR⁶O—;

R³ is —C(═O)OR⁷;

R⁴ is C₁-C₈ alkyl or C₂-C₈ alkenyl, wherein the C₁-C₈ alkyl of R⁴ isoptionally substituted with one or two substituents independentlyselected from carbonyl and —OR⁸;

R⁵ is C₁-C₈ alkyl or C₂-C₈ alkenyl;

R⁷ is C₁-C₂₀ alkyl, C₂-C₈ alkenyl, C₃-C₁₀ carbocyclyl, C₆-C₁₀ aryl, 4 to8 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected fromN, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S;

wherein C₁-C₂₀ alkyl, C₃-C₁₀ carbocyclyl, C₆-C₁₀ aryl, or 4 to 8membered heterocyclyl of R⁷ are each, independently, optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of C₁-C₈ alkyl, halogen, carbonyl, —OR⁸,—NR⁹R¹⁰, —OP(═O)(OH)₂, —OP(═O)(OR⁸)₂, C₃-C₈ carbocyclyl, 4 to 6 memberedheterocyclyl containing 1, 2, or 3 heteroatoms selected from N, O, andS, 5 to 6 membered heteroaryl containing 1, 2, or 3 heteroatoms selectedfrom N, O, and S, and phenyl;

wherein substituent C₃-C₈ carbocyclyl of R⁷ is optionally substitutedwith one or two substituents independently selected from C₁-C₈ alkyl,halogen, —CF₃, cyano, —CH₂CN, and phenyl,

wherein substituent 4 to 6 membered heterocyclyl of R⁷ is optionallysubstituted two substituents independently selected from carbonyl andC₁-C₆ alkyl, and

wherein substituent phenyl of R⁷ is optionally substituted with —OR⁸;

R⁶ is C₁-C₆ alkoxy or C₆-C₁₀ aryl;

each R⁸ is independently H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and 4 to 6membered heterocyclyl;

wherein C₁-C₆ alkyl of R¹ is optionally substituted with C₃-C₆cycloalkyl;

each R⁹ and R¹⁰ are independently C₁-C₆ alkyl;

Base is

R¹¹ is C₁-C₆ alkyl optionally substituted with —OP(═O)(OH)(OR¹⁴);

R¹² is H, —C(═O)R¹³, or —C(═O)OR¹³

each R¹³ is independently C₁-C₈ alkyl optionally substituted with phenylor —OP(═O)(OH)(OR¹⁴); and

each R¹⁴ is independently H or C₁-C₈ alkyl; wherein C₁-C₈ alkyl of R¹⁴is optionally substituted with phenyl.

In some embodiments,

R¹ is —OH, —OC(═O)R⁴, or —OC(═O)OR⁴;

R² is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or

R¹ and R² are taken together to form —OC(═O)O—, —OP(═O)(OH)O—, or—OCR⁶O—;

R³ is —C(═O)OR⁷;

R⁴ is C₁-C₈ alkyl or C₂-C₈ alkenyl, wherein the C₁-C₈ alkyl of R⁴ isoptionally substituted with one or two substituents independentlyselected from carbonyl and —OR⁸;

R⁵ is C₁-C₈ alkyl or C₂-C₈ alkenyl;

R⁷ is C₁-C₂₀ alkyl, C₂-C₈ alkenyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl, 4 to6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected fromN, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S;

-   -   wherein C₁-C₂₀ alkyl, C₃-C₈ carbocyclyl, or C₆-C₁₀ aryl of R⁷        are each, independently, optionally substituted with one, two,        or three substituents independently selected from the group        consisting of C₁-C₈ alkyl, halogen, carbonyl, —OR⁸, —NR⁹R¹⁰,        —OP(═O)(OH)₂, —OP(═O)(OR⁸)₂, C₃-C₈ carbocyclyl, 4 to 6 membered        heterocyclyl containing 1, 2, or 3 heteroatoms selected from N,        O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3        heteroatoms selected from N, O, and S, and phenyl;        -   wherein substituent C₃-C₈ carbocyclyl of R⁷ is optionally            substituted with one or two substituents independently            selected from C₁-C₈ alkyl, halogen, —CF₃, cyano, —CH₂CN, and            phenyl,        -   wherein substituent 4 to 6 membered heterocyclyl of R⁷ is            optionally substituted two substituents independently            selected from carbonyl and C₁-C₆ alkyl, and        -   wherein substituent phenyl of R⁷ is optionally substituted            with —OR⁸;

R⁶ is C₁-C₆ alkoxy or C₆-C₁₀ aryl;

each R⁸ is independently H or C₁-C₆ alkyl;

each R⁹ and R¹⁰ are independently C₁-C₆ alkyl;

Base is

R¹¹ is C₁-C₆ alkyl optionally substituted with —OP(═O)(OH)(OR¹⁴);

R¹² is H, —C(═O)R¹³, or —C(═O)OR¹³

each R¹³ is independently C₁-C₈ alkyl optionally substituted with phenylor —OP(═O)(OH)(OR¹⁴); and

each R¹⁴ is independently H or C₁-C₈ alkyl; wherein C₁-C₈ alkyl of R¹⁴is optionally substituted with phenyl.

In some embodiments,

R¹ is —OH, —OC(═O)R⁴, or —OC(═O)OR⁴;

R² is —OH, —OC(═O)R⁵, or —OC(═O)OR⁵; or

R¹ and R² are taken together to form —OC(═O)O—, —OP(═O)(OH)O—, or—OCR⁶O—;

R³ is —C(═O)OR⁷;

R⁴ and R⁵ are C₁-C₈ alkyl;

R⁷ is C₁-C₂₀ alkyl, C₂-C₈ alkenyl, C₃-C₈ carbocyclyl, C₆-C₁₀ aryl, 4 to6 membered heterocyclyl containing 1, 2, or 3 heteroatoms selected fromN, O, and S, or 5 to 6 membered heteroaryl containing 1, 2, or 3heteroatoms selected from N, O, and S;

-   -   wherein C₁-C₂₀ alkyl, C₃-C₈ carbocyclyl, or C₆-C₁₀ aryl of R⁷        are each, independently, optionally substituted with one, two,        or three substituents independently selected from the group        consisting of C₁-C₈ alkyl, halogen, carbonyl, —OR⁸, —NR⁹R¹⁰,        —OP(═O)(OH)₂, —OP(═O)(OR⁸)₂, C₃-C₈ carbocyclyl, 4 to 6 membered        heterocyclyl containing 1, 2, or 3 heteroatoms selected from N,        O, and S, 5 to 6 membered heteroaryl containing 1, 2, or 3        heteroatoms selected from N, O, and S, and phenyl;        -   wherein substituent C₃-C₈ carbocyclyl of R⁷ is optionally            substituted with one or two substituents independently            selected from C₁-C₈ alkyl, halogen, —CF₃, cyano, —CH₂CN, and            phenyl,        -   wherein substituent 4 to 6 membered heterocyclyl of R⁷ is            optionally substituted two substituents independently            selected from carbonyl and C₁-C₆ alkyl, and        -   wherein substituent phenyl of R⁷ is optionally substituted            with —OR⁸;

R⁶ is C₁-C₆ alkoxy or C₆-C₁₀ aryl;

each R⁸, R⁹, and R¹⁰ are independently C₁-C₆ alkyl;

Base is

R¹¹ is C₁-C₆ alkyl optionally substituted with —OP(═O)(OH)(OR¹⁴);

R¹² is H, —C(═O)R¹³, or —C(═O)OR¹³

each R¹³ is independently C₁-C₈ alkyl optionally substituted with—OP(═O)(OH)(OR¹⁴); and

each R¹⁴ is independently H or C₁-C₈ alkyl; wherein C₁-C₈ alkyl of R¹⁴is optionally substituted with phenyl.

In some embodiments,

R¹ is —OH or —OC(═O)R⁴;

R² is —OH or —OC(═O)R⁵; or

R¹ and R² are taken together to form —OC(═O)O— or —OP(═O)(OH)O—;

R³ is —C(═O)OR⁷;

R⁴, R⁵, and R⁷ are each independently C₁-C₈ alkyl, C₃-C₈ carbocyclyl,C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S or 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S;

-   -   wherein C₁-C₈ alkyl of R⁷ are each, independently, optionally        substituted with one substituent selected from the group        consisting of C₁-C₈ alkyl, —OR⁸, —OP(═O)(OH)₂, C₃-C₈        carbocyclyl, 4 to 6 membered heterocyclyl containing 1, 2, or 3        heteroatoms selected from N, O, and S, 5 to 6 membered        heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O,        and S, and phenyl;        -   wherein 4 to 6 membered heterocyclyl is optionally            substituted with one, two, or three substituents            independently selected from carbonyl and C₁-C₆ alkyl;

each R⁸ is independently C₁-C₆ alkyl;

Base is

R¹¹ is C₁-C₆ alkyl substituted with —OP(═O)(OH)(OR¹⁴);

R¹² is H, —C(═O)R¹³ or —C(═O)OR¹³

R¹³ is C₁-C₈ alkyl optionally substituted with —OP(═O)(OH)(OR¹⁴); and

each R¹⁴ is independently H or C₁-C₈ alkyl; wherein C₁-C₈ alkyl of R¹⁴is optionally substituted with phenyl.

In some embodiments,

R¹ is —OH or —OC(═O)R⁴;

R² is —OH or —OC(═O)R⁵; or

R¹ and R² are taken together to form —OC(═O)O— or —OP(═O)(OH)O—;

R³ is —C(═O)OR⁷;

R⁴, R⁵, and R⁷ are each independently C₁-C₈ alkyl, C₃-C₈ carbocyclyl,C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S or 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S;

-   -   wherein C₁-C₈ alkyl of R⁷ are each, independently, optionally        substituted with one substituent selected from the group        consisting of —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl, 4 to 6        membered heterocyclyl containing 1, 2, or 3 heteroatoms selected        from N, O, and S, 5 to 6 membered heteroaryl containing 1, 2, or        3 heteroatoms selected from N, O, and S, and phenyl;        -   wherein 4 to 6 membered heterocyclyl is optionally            substituted with one, two, or three substituents            independently selected from carbonyl and C₁-C₆ alkyl;

each R⁸ is independently C₁-C₆ alkyl;

Base is

R¹¹ is C₁-C₆ alkyl substituted with —OP(═O)(OH)(OR¹⁴);

R¹² is H, —C(═O)R¹³ or —C(═O)OR¹³

R¹³ is C₁-C₈ alkyl optionally substituted with —OP(═O)(OH)(OR¹⁴); and

each R¹⁴ is independently H or C₁-C₈ alkyl; wherein C₁-C₈ alkyl of R¹⁴is optionally substituted with phenyl.

In some embodiments,

R¹ is —OH or —OC(═O)R⁴;

R² is —OH or —OC(═O)R⁵; or

R¹ and R² are taken together to form —OC(═O)O—;

R³ is —C(═O)OR⁷;

R⁴, R⁵, and R⁷ are each independently C₁-C₈ alkyl, C₃-C₈ carbocyclyl,C₆-C₁₀ aryl, 4 to 6 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S or 5 to 6 membered heteroarylcontaining 1, 2, or 3 heteroatoms selected from N, O, and S;

-   -   wherein C₁-C₈ alkyl of R⁷ are each, independently, optionally        substituted with one substituent selected from the group        consisting of —OR⁸, —OP(═O)(OH)₂, C₃-C₈ carbocyclyl and phenyl;

each R⁸ is independently C₁-C₆ alkyl;

Base is

R¹¹ is C₁-C₆ alkyl substituted with —OP(═O)(OH)(OR¹⁴);

R¹² is H, —C(═O)R¹³ or —C(═O)OR¹³;

R¹³ is C₁-C₈ alkyl; and

each R¹⁴ is independently H or C₁-C₈ alkyl; wherein C₁-C₈ alkyl of R¹⁴is optionally substituted with phenyl.

In some embodiments,

R¹ is —OH or —OC(═O)R⁴;

R² is —OH or —OC(═O)R⁵; or

R¹ and R² are taken together to form —OC(═O)O—;

R³ is —C(═O)OR⁷;

R⁴, R⁵, and R⁷ are each independently C₁-C₈ alkyl, C₃-C₈ carbocyclyl,C₆-C₁₀ aryl, or 4 to 6 membered heterocyclyl containing 1, 2, or 3heteroatoms selected from N, O, and S;

-   -   wherein C₁-C₈ alkyl of R⁷ are each, independently, optionally        substituted with one substituent selected from the group        consisting of —OR⁸ and phenyl;

each R⁸ is independently C₁-C₆ alkyl;

Base is

R¹¹ is C₁-C₆ alkyl substituted with —OP(═O)(OH)(OR¹⁴);

R¹² is H, —C(═O)R¹³ or —C(═O)OR¹³

R¹³ is C₁-C₈ alkyl; and

each R¹⁴ is independently H or C₁-C₈ alkyl; wherein C₁-C₈ alkyl of R¹⁴is optionally substituted with phenyl.

In some embodiments, the compound of Formula I is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

Example No. Compound No. Structure Example 1  1

Example 2  2

Example 3  3

Example 4  4

Example 5  5

Example 6  6

Example 7  7

Example 8  8

Example 9  9

Example 10 10

Example 11 11

Example 12 12

Example 13 13

Example 14 14

Example 15 15

Example 16 16

Example 17 17

Example 18 18

Example 19 19

Example 20 20

Example 21 21

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

Example No Compound No Structure 22

23

24

25

Example 80 26

Example 74 27

28

Example 30 29

30

Example 72 31

32

33

34

Example 38 35

36

Example 81 37

38

39

Example 95 40

41

42

43

44

45

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

Example Compound No. No. Structure Example 22  46

Example 23  47

Example 24  48

Example 25  49

Example 26  50

Example 27  51

Example 28  52

Example 29  53

Example 31  54

Example 32  55

Example 33  56

Example 34  57

Example 35  58

Example 36  59

Example 37  60

Example 39  62

Example 40  63

Example 42  64

Example 43  65

Example 44  66

Example 45  67

Example 46  68

Example 47  69

Example 48  70

Example 49  71

Example 50  72

Example 51  73

Example 52  74

Example 53  75

Example 54  76

Example 55  77

Example 56  78

Example 57  79

Example 58  80

Example 59  81

Example 60  82

Example 61  83

Example 62  84

Example 63  85

Example 64  86

Example 65  87

Example 66  88

Example 67  89

Example 68  90

Example 69  91

Example 70  92

Example 71  93

Example 73  94

Example 75  96

Example 76  97

Example 77  98

Example 78  99

Example 79 100

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

Example No. Compound No. Structure Example 93 101

102

Example 96 103

104

105

Example 92 106

Example 97 107

108

109

Example 94 110

Example 109 111

Example 101 112

Example 102 114

Example 103 115

Example 104 116

Example 105 117

Example 106 118

Example 107 119

Example 99 120

Example 100 121

Example 108 122

Example 109 123

Example 113 124

Example 98 125

Example 114 126

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

Example No. Compound No. Structure Example 82 127

Example 83 128

Example 84 129

Example 85 130

Example 86 131

Example 87 132

Example 88 133

Example 89 134

Example 90 135

Example 91 136

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I is

Example No. Compound No. Structure Example 110 137

Example 111 138

Example 112 139

Example 115 140

Example 116 141

Example 117 142

Example 118 143

Example 119 144

Example 120 145

Example 121 146

Example 122 147

Example 123 148

Example 124 149

Example 125 150

Example 126 151

Example 127 152

Example 128 153

Example 131 154

Example 132 155

Example 133 156

or a pharmaceutically acceptable salt thereof.

V. Pharmaceutical Formulations

The compounds disclosed herein may be formulated with conventionalcarriers and excipients. For example, tablets will contain excipients,glidants, fillers, binders and the like. Aqueous formulations areprepared in sterile form, and when intended for delivery by other thanoral administration generally will be isotonic. All formulations mayoptionally comprise excipients such as those set forth in the “Handbookof Pharmaceutical Excipients” (1986). Pharmaceutically acceptableexcipients include ascorbic acid and other antioxidants, chelatingagents such as EDTA, carbohydrates such as dextran,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike. In some embodiments, the formulations comprise one or morepharmaceutically acceptable excipients. The pH of the formulationsranges from about 3 to about 11, but is ordinarily about 7 to 10. Insome embodiments, the pH of the formulations ranges from about 2 toabout 5, but is ordinarily about 3 to 4.

While it is possible for the compounds of the disclosure (“the activeingredients”) to be administered alone it may be preferable to presentthem as pharmaceutical formulations. The formulations, both forveterinary and for human use, of the invention comprise at least oneactive ingredient, as above defined, together with one or moreacceptable carriers therefor and optionally other therapeuticingredients, particularly those additional therapeutic ingredients asdiscussed herein. The carrier(s) must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation andphysiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any appropriate method known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

In some embodiments, the pharmaceutical formulation is for subcutaneous,intramuscular, intravenous, oral, or inhalation administration.

In some embodiments, the compound described herein e.g., the compound ofFormula I, or the pharmaceutically acceptable salt thereof, describedherein have optimized/improved pharmacokinetic properties and areamenable to oral administration. For example, the compounds of Formula Ihave improved bioavailability and can therefore be administered by oraladministration.

In some embodiments, the formulations of the present invention aresuitable for oral administration may be presented as discrete units suchas capsules, cachets or tablets each containing a predetermined amountof the active ingredient; as a powder or granules; as a solution or asuspension in an aqueous or non-aqueous liquid; or as an oil-in-waterliquid emulsion or a water-in-oil liquid emulsion. The active ingredientmay also be administered as a bolus, electuary or paste.

In some embodiments, the tablet is made by compression or molding,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as a powder or granules,optionally mixed with a binder, lubricant, inert diluent, preservative,surface active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

For infections of the eye or other external tissues, e.g., mouth andskin, the formulations are applied as a topical ointment or creamcontaining the active ingredient(s) in an amount of, for example, 0.075to 20% w/w (including active ingredient(s) in a range between 0.1% and20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e., an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate. Further emulgents and emulsion stabilizers suitable foruse in the formulation of the invention include Tween® 80.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention comprisea compound according to the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets may be uncoated or may be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally-occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate).

The aqueous suspension may also contain one or more preservatives suchas ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents,one or more flavoring agents and one or more sweetening agents, such assucrose or saccharin. Further non-limiting examples of suspending agentsinclude Cyclodextrin. In some examples, the suspending agent isSulfobutyl ether beta-cyclodextrin (SEB-beta-CD), for example Captisol©.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally-occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose, any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution isotonic sodium chloride solution,and hypertonic sodium chloride solution.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 mg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to10%, and particularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

In some embodiments, the compounds disclosed herein are administered byinhalation. In some embodiments, formulations suitable forintrapulmonary or nasal administration have a particle size for examplein the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35 etc., whichis administered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents.

In some embodiments, the compounds used herein are formulated and dosedas dry powder. In some embodiments, the compounds used herein areformulated and dosed as a nebulized formulation. In some embodiments,the compounds used herein are formulated for delivery by a face mask. Insome embodiments, the compounds used herein are formulated for deliveryby a face tent.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use.

Extemporaneous injection solutions and suspensions are prepared fromsterile powders, granules and tablets of the kind previously described.Preferred unit dosage formulations are those containing a daily dose orunit daily sub-dose, as herein above recited, or an appropriate fractionthereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention are used to provide controlled releasepharmaceutical formulations containing as active ingredient one or morecompounds of the invention (“controlled release formulations”) in whichthe release of the active ingredient are controlled and regulated toallow less frequency dosing or to improve the pharmacokinetic ortoxicity profile of a given active ingredient.

VI. Kits

Also provided herein are kits that includes a compound disclosed herein,a pharmaceutically acceptable salt, stereoisomer, mixture ofstereoisomers or tautomer thereof. In some embodiments the kitsdescribed herein may comprise a label and/or instructions for use of thecompound in the treatment of a disease or condition in a subject (e.g.,human) in need thereof. In some embodiments, the disease or condition isviral infection.

In some embodiments, the kit may also comprise one or more additionaltherapeutic agents and/or instructions for use of additional therapeuticagents in combination with the compound of Formula I in the treatment ofthe disease or condition in a subject (e.g., human) in need thereof.

In some embodiments, the kits provided herein comprises individual doseunits of a compound as described herein, or a pharmaceuticallyacceptable salt, racemate, enantiomer, diastereomer, tautomer,polymorph, pseudopolymorph, amorphous form, hydrate or solvate thereof.Examples of individual dosage units may include pills, tablets,capsules, prefilled syringes or syringe cartridges, IV bags, inhalers,nebulizers etc., each comprising a therapeutically effective amount ofthe compound in question, or a pharmaceutically acceptable salt,racemate, enantiomer, diastereomer, tautomer, polymorph,pseudopolymorph, amorphous form, hydrate or solvate thereof. In someembodiments, the kit may contain a single dosage unit and in others,multiple dosage units are present, such as the number of dosage unitsrequired for a specified regimen or period.

Also provided are articles of manufacture that include a compound ofFormula I, or a pharmaceutically acceptable salt, stereoisomer, mixtureof stereoisomers or tautomer thereof, and a container. In someembodiments, the container of the article of manufacture is a vial, jar,ampoule, preloaded syringe, blister package, tin, can, bottle, box, anintravenous bag, an inhaler, or a nebulizer.

VII. Administration

One or more compounds of the invention are administered by any routeappropriate to the condition to be treated. Suitable routes includeoral, rectal, inhalation, pulmonary, topical (including buccal andsublingual), vaginal and parenteral (including subcutaneous,intramuscular, intravenous, intradermal, intrathecal and epidural), andthe like. In some embodiments, the compounds disclosed herein areadministered by inhalation or intravenously. In some embodiments, thecompounds disclosed herein are administered orally. It will beappreciated that the preferred route may vary with for example thecondition of the recipient.

In the methods of the present invention for the treatment of a viralinfection, the compounds of the present invention can be administered atany time to a human who may come into contact with the virus or isalready suffering from the viral infection. In some embodiments, thecompounds of the present invention can be administered prophylacticallyto humans coming into contact with humans suffering from the viralinfection or at risk of coming into contact with humans suffering fromthe viral infection, e.g., healthcare providers. In some embodiments,administration of the compounds of the present invention can be tohumans testing positive for the viral infection but not yet showingsymptoms of the viral infection. In some embodiments, administration ofthe compounds of the present invention can be to humans uponcommencement of symptoms of the viral infection.

In some embodiments, the methods disclosed herein comprise event drivenadministration of the compound described herein, e.g., the compound ofFormula I, or a pharmaceutically acceptable salt thereof, to thesubject.

As used herein, the terms “event driven” or “event drivenadministration” refer to administration of the compound described herein(e.g., the compound of Formula I), or a pharmaceutically acceptable saltthereof, (1) prior to an event (e.g., 2 hours, 1 day, 2 days, 5 day, or7 or more days prior to the event) that would expose the individual tothe virus (or that would otherwise increase the individual's risk ofacquiring the viral infection); and/or (2) during an event (or more thanone recurring event) that would expose the individual to the virus (orthat would otherwise increase the individual's risk of acquiring theviral infection); and/or (3) after an event (or after the final event ina series of recurring events) that would expose the individual to thevirus (or that would otherwise increase the individual's risk ofacquiring the viral infection). In some embodiments, the event drivenadministration is performed pre-exposure of the subject to the virus. Insome embodiments, the event driven administration is performedpost-exposure of the subject to the virus. In some embodiments, theevent driven administration is performed pre-exposure of the subject tothe virus and post-exposure of the subject to the virus.

In certain embodiments, the methods disclosed herein involveadministration prior to and/or after an event that would expose theindividual to the virus or that would otherwise increase theindividual's risk of acquiring the viral infection, e.g., aspre-exposure prophylaxis (PrEP) and/or as post-exposure prophylaxis(PEP). In some embodiments, the methods disclosed herein comprisepre-exposure prophylaxis (PrEP). In some embodiments, methods disclosedherein comprise post-exposure prophylaxis (PEP).

In some embodiments, the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is administered before exposure of the subjectto the virus.

In some embodiments, the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is administered before and after exposure ofthe subject to the virus.

In some embodiments, the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, is administered after exposure of the subjectto the virus.

An example of event driven dosing regimen includes administration of thecompound of Formula I, or a pharmaceutically acceptable salt thereof,within 24 to 2 hours prior to the virus, followed by administration ofthe compound of Formula I, or a pharmaceutically acceptable salt, every24 hours during the period of exposure, followed by a furtheradministration of the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, after the last exposure, and one lastadministration of the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, 24 hours later.

A further example of an event driven dosing regimen includesadministration of the compound of Formula I, or a pharmaceuticallyacceptable salt thereof, within 24 hours before the viral exposure, thendaily administration during the period of exposure, followed by a lastadministration approximately 24 hours later after the last exposure(which may be an increased dose, such as a double dose).

The specific dose level of a compound of the present disclosure for anyparticular subject will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the subject undergoing therapy. Forexample, a dosage may be expressed as a number of milligrams of acompound described herein per kilogram of the subject's body weight(mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate.In some embodiments, about 0.1 and 100 mg/kg may be appropriate. Inother embodiments a dosage of between 0.5 and 60 mg/kg may beappropriate. Normalizing according to the subject's body weight isparticularly useful when adjusting dosages between subjects of widelydisparate size, such as occurs when using the drug in both children andadult humans or when converting an effective dosage in a non-humansubject such as dog to a dosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compounddescribed herein administered per dose or per day. Daily dosage of acompound of Formula I, or a pharmaceutically acceptable salt thereof,may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day,between about 50 to 300 mg/day, between about 75 to 200 mg/day, orbetween about 15 to 150 mg/day.

The dosage or dosing frequency of a compound of the present disclosuremay be adjusted over the course of the treatment, based on the judgmentof the administering physician.

The compounds of the present disclosure may be administered to anindividual (e.g., a human) in a therapeutically effective amount. Insome embodiments, the compound is administered once daily.

The compounds provided herein can be administered by any useful routeand means, such as by oral or parenteral (e.g., intravenous)administration. Therapeutically effective amounts of the compound mayinclude from about 0.00001 mg/kg body weight per day to about 10 mg/kgbody weight per day, such as from about 0.0001 mg/kg body weight per dayto about 10 mg/kg body weight per day, or such as from about 0.001 mg/kgbody weight per day to about 1 mg/kg body weight per day, or such asfrom about 0.01 mg/kg body weight per day to about 1 mg/kg body weightper day, or such as from about 0.05 mg/kg body weight per day to about0.5 mg/kg body weight per day. In some embodiments, a therapeuticallyeffective amount of the compounds provided herein include from about 0.3mg to about 30 mg per day, or from about 30 mg to about 300 mg per day,or from about 0.3 mg to about 30 mg per day, or from about 30 mg toabout 300 mg per day.

A compound of the present disclosure may be combined with one or moreadditional therapeutic agents in any dosage amount of the compound ofthe present disclosure (e.g., from 1 mg to 1000 mg of compound).Therapeutically effective amounts may include from about 0.1 mg per doseto about 1000 mg per dose, such as from about 50 mg per dose to about500 mg per dose, or such as from about 100 mg per dose to about 400 mgper dose, or such as from about 150 mg per dose to about 350 mg perdose, or such as from about 200 mg per dose to about 300 mg per dose, orsuch as from about 0.01 mg per dose to about 1000 mg per dose, or suchas from about 0.01 mg per dose to about 100 mg per dose, or such as fromabout 0.1 mg per dose to about 100 mg per dose, or such as from about 1mg per dose to about 100 mg per dose, or such as from about 1 mg perdose to about 10 mg per dose, or such as from about 1 mg per dose toabout 1000 mg per dose. Other therapeutically effective amounts of thecompound of Formula I are about 1 mg per dose, or about 2, 3, 4, 5, 6,7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,90, 95, or about 100 mg per dose. Other therapeutically effectiveamounts of the compound of the present disclosure are about 100, 125,150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475,500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825,850, 875, 900, 925, 950, 975, or about 1000 mg per dose.

In some embodiments, the methods described herein comprise administeringto the subject an initial daily dose of about 1 to 500 mg of a compoundprovided herein and increasing the dose by increments until clinicalefficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg canbe used to increase the dose. The dosage can be increased daily, everyother day, twice per week, once per week, once every two weeks, onceevery three weeks, or once a month.

When administered orally, the total daily dosage for a human subject maybe between about 1-4,000 mg/day, between about 1-3,000 mg/day, between1-2,000 mg/day, about 1-1,000 mg/day, between about 10-500 mg/day,between about 50-300 mg/day, between about 75-200 mg/day, or betweenabout 100-150 mg/day. In some embodiments, the total daily dosage for ahuman subject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900,1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100,2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or 3000 mg/dayadministered in a single dose. In some embodiments, the total dailydosage for a human subject may be about 200, 300, 400, 500, 600, 700, or800 mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 300, 400, 500, or 600mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 100, 200, 300, 400, 500,600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700,1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900,3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, or 4000mg/day. In some embodiments, the total daily dosage for a human subjectmay be about 100-200, 100-300, 100-400, 100-500, 100-600, 100-700,100-800, 100-900, 100-1000, 500-1100, 500-1200, 500-1300, 500-1400,500-1500, 500-1600, 500-1700, 500-1800, 500-1900, 500-2000, 1500-2100,1500-2200, 1500-2300, 1500-2400, 1500-2500, 2000-2600, 2000-2700,2000-2800, 2000-2900, 2000-3000, 2500-3100, 2500-3200, 2500-3300,2500-3400, 2500-3500, 3000-3600, 3000-3700, 3000-3800, 3000-3900, or3000-4000 mg/day.

In some embodiments, the total daily dosage for a human subject may beabout 100 mg/day administered in a single dose. In some embodiments, thetotal daily dosage for a human subject may be about 150 mg/dayadministered in a single dose. In some embodiments, the total dailydosage for a human subject may be about 200 mg/day administered in asingle dose. In some embodiments, the total daily dosage for a humansubject may be about 250 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 300mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 350 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 400 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 450mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 500 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 550 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 600mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 650 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 700 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 750mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 800 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 850 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about 900mg/day administered in a single dose. In some embodiments, the totaldaily dosage for a human subject may be about 950 mg/day administered ina single dose. In some embodiments, the total daily dosage for a humansubject may be about 1000 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about1500 mg/day administered in a single dose. In some embodiments, thetotal daily dosage for a human subject may be about 2000 mg/dayadministered in a single dose. In some embodiments, the total dailydosage for a human subject may be about 2500 mg/day administered in asingle dose. In some embodiments, the total daily dosage for a humansubject may be about 3000 mg/day administered in a single dose. In someembodiments, the total daily dosage for a human subject may be about4000 mg/day administered in a single dose.

A single dose can be administered hourly, daily, weekly, or monthly. Forexample, a single dose can be administered once every 1 hour, 2, 3, 4,6, 8, 12, 16 or once every 24 hours. A single dose can also beadministered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. Asingle dose can also be administered once every 1 week, 2, 3, or onceevery 4 weeks. In certain embodiments, a single dose can be administeredonce every week. A single dose can also be administered once everymonth. In some embodiments, a compound disclosed herein is administeredonce daily in a method disclosed herein. In some embodiments, a compounddisclosed herein is administered twice daily in a method disclosedherein. In some embodiments, a compound disclosed herein is administeredthree times daily in a method disclosed herein.

In some embodiments, a compound disclosed herein is administered oncedaily in the total daily dose of 100-4000 mg/day. In some embodiments, acompound disclosed herein is administered twice daily in the total dailydose of 100-4000 mg/day. In some embodiments, a compound disclosedherein is administered three times daily in the total daily dose of100-4000 mg/day.

The frequency of dosage of the compound of the present disclosure willbe determined by the needs of the individual patient and can be, forexample, once per day or twice, or more times, per day. Administrationof the compound continues for as long as necessary to treat the viralinfection. For example, a compound can be administered to a human beinginfected with the virus for a period of from 20 days to 180 days or, forexample, for a period of from 20 days to 90 days or, for example, for aperiod of from 30 days to 60 days.

Administration can be intermittent, with a period of several or moredays during which a patient receives a daily dose of the compound of thepresent disclosure followed by a period of several or more days duringwhich a patient does not receive a daily dose of the compound. Forexample, a patient can receive a dose of the compound every other day,or three times per week.

Again by way of example, a patient can receive a dose of the compoundeach day for a period of from 1 to 14 days, followed by a period of 7 to21 days during which the patient does not receive a dose of thecompound, followed by a subsequent period (e.g., from 1 to 14 days)during which the patient again receives a daily dose of the compound.Alternating periods of administration of the compound, followed bynon-administration of the compound, can be repeated as clinicallyrequired to treat the patient.

The compounds of the present disclosure or the pharmaceuticalcompositions thereof may be administered once, twice, three, or fourtimes daily, using any suitable mode described above.

Also, administration or treatment with the compounds may be continuedfor a number of days; for example, commonly treatment would continue forat least 7 days, 14 days, or 28 days, for one cycle of treatment.Treatment cycles are well known in cancer chemotherapy, and arefrequently alternated with resting periods of about 1 to 28 days,commonly about 7 days or about 14 days, between cycles. The treatmentcycles, in other embodiments, may also be continuous.

VIII. Methods of Use

The present disclosure also provides a method of treating or preventinga viral infection in a subject (e.g., human) in need thereof, the methodcomprising administering to the subject a compound described herein.

In some embodiments, the present disclosure provides a method oftreating a viral infection in a subject (e.g., human) in need thereof,the method comprising administering to a subject in need thereof acompound described herein.

In some embodiments, the compound described herein is administered tothe human via oral, intramuscular, intravenous, subcutaneous, orinhalation administration.

In some embodiments, the present disclosure provides for methods oftreating or preventing a viral infection in a subject (e.g., human) inneed thereof, the method comprising administering to the subject acompound disclosed herein and at least one additional active therapeuticor prophylactic agent.

In some embodiments, the present disclosure provides for methods oftreating a viral infection in a subject (e.g., human) in need thereof,the method comprising administering to the subject a compound disclosedherein, and at least one additional active therapeutic or prophylacticagent.

In one embodiment, the present disclosure provides for methods ofinhibiting a viral polymerase in a cell, the methods comprisingcontacting the cell infected a virus with a compound disclosed herein,whereby the viral polymerase is inhibited.

In one embodiment, the present disclosure provides for methods ofinhibiting a viral polymerase in a cell, the methods comprisingcontacting the cell infected a virus with a compound disclosed herein,and at least one additional active therapeutic agent, whereby the viralpolymerase is inhibited.

Also provided here are the uses of the compounds disclosed herein foruse in treating or preventing a viral infection in a subject in needthereof. For example, provided herein are uses of the compoundsdisclosed herein for use in treating a viral infection in a subject inneed thereof.

In some embodiments, the viral infection is a paramyxoviridae virusinfection. As such, in some embodiments, the present disclosure providesmethods for treating a paramyxoviridae infection in a subject (e.g., ahuman) in need thereof, the method comprising administering to thesubject a compound disclosed herein. Paramyxoviridae viruses include,but are not limited to Nipah virus, Hendra virus, measles, mumps, andparainfluenze virus.

In some embodiments, the viral infection is a human parainfluenza virus,Nipah virus, Hendra virus, measles, or mumps infection.

In some embodiments, the viral infection is a pneumoviridae virusinfection. As such, in some embodiments, the present disclosure providesa method of treating a pneumoviridae virus infection in a human in needthereof, the method comprising administering to the human a compoundprovided herein. Pneumoviridae viruses include, but are not limited to,respiratory snycytial virus and human metapneumovirus. In someembodiments, the pneumoviridae virus infection is a respiratorysyncytial virus infection. In some embodiments, the pneumoviridae virusinfection is human metapneumovirus infection.

In some embodiments, the present disclosure provides a compounddisclosed herein, for use in the treatment of a pneumoviridae virusinfection in a human in need thereof. In some embodiments, thepneumoviridae virus infection is a respiratory syncytial virusinfection. In some embodiments, the pneumoviridae virus infection ishuman metapneumovirus infection.

In some embodiments, the present disclosure provides methods fortreating a RSV infection in a human in need thereof, the methodcomprising administering to the human a compound provided herein. Insome embodiments, the human is suffering from a chronic respiratorysyncytial viral infection. In some embodiments, the human is acutelyinfected with RSV.

In some embodiments, a method of inhibiting RSV replication is provided,wherein the method comprises administering to a human in need thereof, acompound disclosed herein, wherein the administration is by inhalation.

In some embodiments, the present disclosure provides a method forreducing the viral load associated with RSV infection, wherein themethod comprises administering to a human infected with RSV a compounddisclosed herein.

In some embodiments, the viral infection is a picornaviridae virusinfection. As such, in some embodiments, the present disclosure providesa method of treating a picornaviridae virus infection in a human in needthereof, the method comprising administering to the human a compound ofthe present disclosure. Picornaviridae viruses are eneterovirusescausing a heterogeneous group of infections including herpangina,aseptic meningitis, a common-cold-like syndrome (human rhinovirusinfection), a non-paralytic poliomyelitis-like syndrome, epidemicpleurodynia (an acute, febrile, infectious disease generally occurringin epidemics), hand-foot-mouth syndrome, pediatric and adultpancreatitis and serious myocarditis. In some embodiments, thePicornaviridae virus infection is human rhinovirus infection (HRV). Insome embodiments, the Picornaviridae virus infection is HRV-A, HRV-B, orHRV-C infection.

In some embodiments, the viral infection is selected from the groupconsisting of Coxsackie A virus infection, Coxsackie A virus infection,enterovirus D68 infection, enterovirus B69 infection, enterovirus D70infection, enterovirus A71 infection, and poliovirus infection.

In some embodiments, the present disclosure provides a compound, for usein the treatment of a picornaviridae virus infection in a human in needthereof. In some embodiments, the picornaviridae virus infection ishuman rhinovirus infection.

In some embodiments, the viral infection is a flaviviridae virusinfection. As such, in some embodiments, the present disclosure providesa method of treating a flaviviridae virus infection in a human in needthereof, the method comprising administering to the human a compounddescribed herein. Representative flaviviridae viruses include, but arenot limited to, dengue, Yellow fever, West Nile, Zika, Japaneseencephalitis virus, and Hepatitis C (HCV). In some embodiments, theflaviviridae virus infection is a dengue virus infection. In someembodiments, the flaviviridae virus infection is a yellow fever virusinfection. In some embodiments, the flaviviridae virus infection is aWest Nile virus infection. In some embodiments, the flaviviridae virusinfection is a zika virus infection. In some embodiments, theflaviviridae virus infection is a Japanese ensephalitis virus infection.In some embodiments, the flaviviridae virus infection is a hepatitis Cvirus infection.

In some embodiments, the flaviviridae virus infection is a dengue virusinfection, yellow fever virus infection, West Nile virus infection, tickborne encephalitis, Kunjin Japanese encephalitis, St. Louisencephalitis, Murray valley encephalitis, Omsk hemorrhagic fever, bovineviral diarrhea, zika virus infection, or a HCV infection.

In some embodiments, the present disclosure provides use of a compounddisclosed herein for treatment of a flaviviridae virus infection in ahuman in need thereof. In some embodiments, the flaviviridae virusinfection is a dengue virus infection. In some embodiments, theflaviviridae virus infection is a yellow fever virus infection. In someembodiments, the flaviviridae virus infection is a West Nile virusinfection. In some embodiments, the flaviviridae virus infection is azika virus infection. In some embodiments, the flaviviridae virusinfection is a hepatitis C virus infection.

In some embodiments, the viral infection is a filoviridae virusinfection. As such, in some embodiments, provided herein is a method oftreating a filoviridae virus infection in a human in need thereof, themethod comprising administering to the human a compound disclosedherein. Representative filoviridae viruses include, but are not limitedto, ebola (variants Zaire, Bundibugio, Sudan, Tai forest, or Reston) andmarburg. In some embodiments, the filoviridae virus infection is anebola virus infection. In some embodiments, the filoviridae virusinfection is a marburg virus infection.

In some embodiments, the present disclosure provides a compound for usein the treatment of a filoviridae virus infection in a human in needthereof. In some embodiments, the filoviridae virus infection is anebola virus infection. In some embodiments, the filoviridae virusinfection is a marburg virus infection.

In some embodiments, the viral infection is a coronavirus infection. Assuch, in some embodiments, provided herein is a method of treating acoronavirus infection in a human in need thereof, wherein the methodcomprises administering to the human a compound provided herein.

In some embodiments, the coronavirus infection is a Severe AcuteRespiratory Syndrome (SARS-CoV) infection, Middle Eastern RespiratorySyndrome (MERS) infection, SARS-CoV-2 infection, other human coronavirus(229E, NL63, OC43, HKU1, or WIV1) infections, zoonotic coronavirus (PEDVor HKU CoV isolates such as HKU3, HKU5, or HKU9) infections. In someembodiments, the viral infection is a Severe Acute Respiratory Syndrome(SARS) infection. In some embodiments, the viral infection is a MiddleEastern Respiratory Syndrome (MERS) infection. In some embodiments, theviral infection is SARS-CoV-2 infection. In some embodiments, the viralinfection is a zoonotic coronavirus infection, In some embodiments, theviral infection is caused by a virus having at least 70% sequencehomology to a viral polymerase selected from the group consisting ofSARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2. In someembodiments, the viral infection is caused by a virus having at least80% sequence homology to a viral polymerase selected from the groupconsisting of SARS-CoV polymerase, MERS-CoV polymerase and SARS-CoV-2.In some embodiments, the viral infection is caused by a virus having atleast 90% sequence homology to a viral polymerase selected from thegroup consisting of SARS-CoV polymerase, MERS-CoV polymerase andSARS-CoV-2. In some embodiments, the viral infection is caused by avirus having at least 95% sequence homology to a viral polymeraseselected from the group consisting of SARS-CoV polymerase, MERS-CoVpolymerase and SARS-CoV-2.

In some embodiments, the viral infection is caused by a variant ofSARS-CoV-2, for example by the B.1.1.7 variant (the UK variant), B.1.351variant (the South African variant), P.1 variant (the Brazil variant),B.1.1.7 with E484K variant, B.1.1.207 variant, B.1.1.317 variant,B.1.1.318 variant, B.1.429 variant, B.1.525 variant, or P.3 variant. Insome embodiments, the viral infection is caused by the B.1.1.7 variantof SARS-CoV-2. In some embodiments, the viral infection is caused by theB.1.351 variant of SARS-CoV-2. In some embodiments, the viral infectionis caused by the P.1 variant of SARS-CoV-2.

In some embodiments, the present disclosure provides a compound for usein the treatment of a coronavirus virus infection in a human in needthereof. In some embodiments, the coronavirus infection is a SevereAcute Respiratory Syndrome (SARS) infection, Middle Eastern RespiratorySyndrome (MERS) infection, SARS-CoV-2 infection, other human coronavirus(229E, NL63, OC43, HKU1, or WIV1) infections, and zoonotic coronavirus(PEDV or HKU CoV isolates such as HKU3, HKU5, or HKU9) infections. Insome embodiments, the viral infection is a Severe Acute RespiratorySyndrome (SARS) infection. In some embodiments, the viral infection is aMiddle Eastern Respiratory Syndrome (MERS) infection. In someembodiments, the viral infection is SARS-CoV-2 infection (COVID19).

In some embodiments, the viral infection is an arenaviridae virusinfection. As such, in some embodiments, the disclosure provides amethod of treating an arenaviridae virus infection in a human in needthereof, the method comprising administering to the human a compounddisclosed herein. In some embodiments, the arenaviridae virus infectionis a Lassa infection or a Junin infection.

In some embodiments, the present disclosure provides a compound for usein the treatment of an arenaviridae virus infection in a human in needthereof. In some embodiments, the arenaviridae virus infection is aLassa infection or a Junin infection.

In some embodiments, the viral infection is an orthomyxovirus infection,for example, an influenza virus infection. In some embodiments, theviral infection is an influenza virus A, influenza virus B, or influenzavirus C infection.

As described more fully herein, the compounds described herein can beadministered with one or more additional therapeutic agent(s) to anindividual (e.g., a human) infected with a viral infection. Theadditional therapeutic agent(s) can be administered to the infectedindividual at the same time as the compound of the present disclosure orbefore or after administration of the compound of the presentdisclosure.

IX. Combination Therapy

The compounds described herein can also be used in combination with oneor more additional therapeutic agents. As such, also provided herein aremethods of treatment of a viral infection in a subject in need thereof,wherein the methods comprise administering to the subject a compounddisclosed therein and a therapeutically effective amount of one or moreadditional therapeutic or prophylactic agents.

In some embodiments, the additional therapeutic agent is an antiviralagent. Any suitable antiviral agent can be used in the methods describedherein. In some embodiments, the antiviral agent is selected from thegroup consisting of 5-substituted 2′-deoxyuridine analogues, nucleosideanalogues, pyrophosphate analogues, nucleoside reverse transcriptaseinhibitors, non-nucleoside reverse transcriptase inhibitors, proteaseinhibitors, integrase inhibitors, entry inhibitors, acyclic guanosineanalogues, acyclic nucleoside phosphonate analogues, HCV NS5A/NS5Binhibitors, influenza virus inhibitors, interferons, immunostimulators,oligonucleotides, antimitotic inhibitors, and combinations thereof.

In some embodiments, the additional therapeutic agent is a 5-substituted2′-deoxyuridine analogue. For example, in some embodiments, theadditional therapeutic agent is selected from the group consisting ofidoxuridine, trifluridine, brivudine [BVDU], and combinations thereof.

In some embodiments, the additional therapeutic agent is a nucleosideanalogue. For example, in some embodiments, the additional therapeuticagent is selected from the group consisting of vidarabine, entecavir(ETV), telbivudine, lamivudine, adefovir dipivoxil, tenofovir disoproxilfumarate (TDF) and combinations thereof. In some embodiments, theadditional therapeutic agent is favipiravir, ribavirin, galidesivir,β-D-N4-hydroxycytidine or a combination thereof.

In some embodiments, the additional therapeutic agent is a pyrophosphateanalogue. For example, in some embodiments, the additional therapeuticagent is foscarnet or phosphonoacetic acid. In some embodiments, theadditional therapeutic agent is foscarnet.

In some embodiments, the additional therapeutic agent is nucleosidereverse transcriptase inhibitor. In some embodiments, the antiviralagent is zidovudine, didanosine, zalcitabine, stavudine, lamivudine,abacavir, emtricitabine, and combinations thereof.

In some embodiments, the additional therapeutic agent is anon-nucleoside reverse transcriptase inhibitor. In some embodiments, theantiviral agent is selected from the group consisting of nevirapine,delavirdine, efavirenz, etravirine, rilpivirine, and combinationsthereof.

In some embodiments, the additional therapeutic agent is a proteaseinhibitor. In some embodiments, the protease inhibitor is a HIV proteaseinhibitor. For example, in some embodiments, the antiviral agent isselected from the group consisting of saquinavir, ritonavir, indinavir,nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir,tipranavir, cobicistat, and combinations thereof. In some embodiments,the antiviral agent is selected from the group consisting of saquinavir,ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir,fosamprenavir, darunavir, tipranavir, and combinations thereof. In someembodiments, the protease inhibitor is a HCV NS3/4A protease inhibitor.For example, in some embodiments, the additional therapeutic agent isselected from the group consisting of voxilaprevir, asunaprevir,boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir,grazoprevir, ribavirin, danoprevir, faldaprevir, vedroprevir,sovaprevir, deldeprevir, narlaprevir and combinations thereof. In someembodiments, the additional therapeutic agent is selected from the groupconsisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir,simeprevir, telaprevir, vaniprevir, grazoprevir, and combinationsthereof.

In some embodiments, the additional therapeutic agent is an integraseinhibitor. For example, in some embodiments, the additional therapeuticagent is selected from the group consisting of raltegravir,dolutegravir, elvitegravir, abacavir, lamivudine, and combinationsthereof. In some embodiments, the additional therapeutic agent isselected from the group consisting of bictegravir, raltegravir,dolutegravir, cabotegravir, elvitegravir, and combinations thereof. Insome embodiments, the additional therapeutic agent is selected from thegroup consisting of bictegravir, dolutegravir, and cabotegravir, andcombinations thereof. In some embodiments, the additional therapeuticagent is bictegravir.

In some embodiments, the additional therapeutic agent is an entryinhibitor. For example, in some embodiments, the additional therapeuticagent is selected from the group consisting of docosanol, enfuvirtide,maraviroc, ibalizumab, fostemsavir, leronlimab, ibalizumab, fostemsavir,leronlimab, palivizumab, respiratory syncytial virus immune globulin,intravenous [RSV-IGIV], varicella-zoster immunoglobulin [VariZIG],varicella-zoster immune globulin [VZIG]), and combinations thereof.

In some embodiments, the additional therapeutic agent is an acyclicguanosine analogue. For example, in some embodiments, the additionaltherapeutic agent is selected from the group consisting of acyclovir,ganciclovir, valacyclovir (also known as valaciclovir), valganciclovir,penciclovir, famciclovir, and combinations thereof.

In some embodiments, the additional therapeutic agent is an acyclicnucleoside phosphonate analogue. For example, in some embodiments, theadditional therapeutic agent is selected from a group consisting ofcidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF, emtricitabine,efavirenz, rilpivirine, elvitegravir, and combinations thereof. In someembodiment, the additional therapeutic agent is selected from the groupconsisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF,and combinations thereof. In some embodiment, the additional therapeuticagent is selected from the group consisting of cidofovir, adefovirdipivoxil, TDF, and combinations thereof.

In some embodiments, the additional therapeutic agent is a HCV NS5A/NS5Binhibitor. In some embodiments, the additional therapeutic agent is aNS3/4A protease inhibitor. In some embodiments, the additionaltherapeutic agent is a NS5A protein inhibitor. In some embodiments, theadditional therapeutic agent is a NS5B polymerase inhibitor of thenucleoside/nucleotide type. In some embodiments, the additionaltherapeutic agent is a NS5B polymerase inhibitor of the nonnucleosidetype. In some embodiments, the additional therapeutic agent is selectedfrom the group consisting of daclatasvir, ledipasvir, velpatasvir,ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir,simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, AT-527, andcombinations thereof. In some embodiments, the additional therapeuticagent is selected from the group consisting of daclatasvir, ledipasvir,velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, andcombinations thereof.

In some embodiments, the additional therapeutic agent is an influenzavirus inhibitor. In some embodiments, the additional therapeutic agentis a matrix 2 inhibitor. For example, in some embodiments, theadditional therapeutic agent is selected from the group consisting ofamantadine, rimantadine, and combinations thereof. In some embodiments,the additional therapeutic agent is a neuraminidase inhibitor. Forexample, in some embodiments, the additional therapeutic agent isselected from the group consisting of zanamivir, oseltamivir, peramivir,laninamivir octanoate, and combinations thereof. In some embodiments,the additional therapeutic agent is a polymerase inhibitor. For example,in some embodiments, the additional therapeutic agent is selected fromthe group consisting of ribavirin, favipiravir, and combinationsthereof. In some embodiments, the additional therapeutic agent isselected from the group consisting of amantadine, rimantadine, arbidol(umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirin,laninamivir octanoate, zanamivir, favipiravir, ribavirin, andcombinations thereof. In some embodiments, the additional therapeuticagent is selected from the group consisting of amantadine, rimantadine,zanamivir, oseltamivir, peramivir, laninamivir octanoate, ribavirin,favipiravir, and combinations thereof.

In some embodiments, the additional therapeutic agent is an interferon.In some embodiments, the additional therapeutic agent is selected fromthe group consisting of interferon alfacon 1, interferon alfa 1b,interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon 1,pegylated interferon alfa 1b, pegylated interferon alfa 2a (PegIFNα-2a),and PegIFNα-2b. e embodiments, the additional therapeutic agent isselected from the group consisting of interferon alfacon 1, interferonalfa 1b, interferon alfa 2a, interferon alfa 2b, pegylated interferonalfa 2a (PegIFNα-2a), and PegIFNα-2b. In some embodiments, theadditional therapeutic agent is selected from the group consisting ofinterferon alfacon 1, pegylated interferon alfa 2a (PegIFNα-2a),PegIFNα-2b, and ribavirin. In some embodiments, the additionaltherapeutic agent is pegylated interferon alfa-2a, pegylated interferonalfa-2b, or a combination thereof.

In some embodiments, the additional therapeutic agent is animmunostimulatory agent. In some embodiments, the additional therapeuticagent is an oligonucleotide. In some embodiments, the additionaltherapeutic agent is an antimitotic inhibitor. For example, in someembodiments, the additional therapeutic agent is selected from the groupconsisting of fomivirsen, podofilox, imiquimod, sinecatechins, andcombinations thereof.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of besifovir, nitazoxanide, REGN2222, doravirine,sofosbuvir, velpatasvir, daclatasvir, asunaprevir, beclabuvir, FV100,and letermovir, and combinations thereof.

In some embodiments, the additional therapeutic agent is an agent fortreatment of RSV. For example, in some embodiments, the antiviral agentis ribavirin, ALS-8112 or presatovir. For example, in some embodiments,the antiviral agent is ALS-8112 or presatovir.

In some embodiments, the additional therapeutic agent is an agent fortreatment of picornavirus. In some embodiments, the additionaltherapeutic agent is selected from the group consisting of hydantoin,guanidine hydrochloride, L-buthionine sulfoximine, Py-11, andcombinations thereof. In some embodiments, the additional therapeuticagent is a picornavirus polymerase inhibitor. In some embodiments, theadditional therapeutic agent is rupintrivir.

In some embodiments, the additional therapeutic agent is an agent fortreatment of malaria. In some embodiments, the additional therapeuticagent is chloroquine.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of hydroxychloroquine, chloroquine, artemether,lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine,artesunate, artenimol, piperaquine, artesunate, amodiaquine,pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine,solithromycin, pyrimethamine, MMV-390048, ferroquine, artefenomelmesylate, ganaplacide, DSM-265, cipargamin, artemisone, and combinationsthereof.

In some embodiments, the additional therapeutic agent is an agent fortreatment of coronavirus. In some embodiments, the additionaltherapeutic agent is selected from a group consisting of IFX-1, FM-201,CYNK-001, DPP4-Fc, ranpirnase, nafamostat, LB-2, AM-1, anti-viroporins,and combinations thereof.

In some embodiments, the additional therapeutic agent is an agent fortreatment of ebola virus. For example, in some embodiments, theadditional therapeutic agent is selected from the group consisting ofribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam©), MEDI-557,A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, EbolaConvalescent Plasma (ECP), TKM-100201, BCX4430((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol),favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705diphosphate, T-705 triphosphate, FGI-106(1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h]quinolone-1,7-diamine),JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BNfilo, brincidofovir, Vaxart adenovirus vector 5-based ebola vaccine,Ad26-ZEBOV, FiloVax vaccine, GOVX-E301, GOVX-E302, ebola virus entryinhibitors (NPC1 inhibitors), rVSV-EBOV, and combinations thereof. Insome embodiments, the additional therapeutic agent is ZMapp, mAB114,REGEN-EB3, and combinations thereof.

In some embodiments, the additional therapeutic agent is an agent fortreatment of HCV. In some embodiments, the additional therapeutic agentis a HCV polymerase inhibitor. For example, in some embodiments, theadditional therapeutic agent is selected from the group consisting ofsofosbuvir, GS-6620, PSI-938, ribavirin, tegobuvir, radalbuvir, MK-0608,and combinations thereof. In some embodiments, the additionaltherapeutic agent is a HCV protease inhibitor. For example, in someembodiments, the additional therapeutic agent is selected from the groupconsisting of such as GS-9256, vedroprevir, voxilaprevir, andcombinations thereof.

In some embodiments, the additional therapeutic agent is a NS5Ainhibitor. For example, in some embodiments, the additional therapeuticagent is selected from the group consisting of ledipasvir, velpatasvir,and combinations thereof.

In some embodiments, the additional therapeutic agent is an anti HBVagent. For example, in some embodiments, the additional therapeuticagent is tenofovir disoproxil fumarate and emtricitabine, or acombination thereof. Examples of additional anti HBV agents include butare not limited to alpha-hydroxytropolones, amdoxovir, antroquinonol,beta-hydroxycytosine nucleosides, ARB-199, CCC-0975, ccc-R08,elvucitabine, ezetimibe, cyclosporin A, gentiopicrin (gentiopicroside),HH-003, hepalatide, JNJ-56136379, nitazoxanide, birinapant, NJK14047,NOV-205 (molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131,levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai),rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA,cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-0061A,Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai (Ganxikang),MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai,IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834,QL-007sofosbuvir, ledipasvir, UB-551, and ZH-2N, and the compoundsdisclosed in US20150210682, (Roche), US 2016/0122344 (Roche),WO2015173164, WO2016023877, US2015252057A (Roche), WO16128335A1 (Roche),WO16120186A1 (Roche), US2016237090A (Roche), WO16107833A1 (Roche),WO16107832A1 (Roche), US2016176899A (Roche), WO16102438A1 (Roche),WO16012470A1 (Roche), US2016220586A (Roche), and US2015031687A (Roche).In some embodiments, the additional therapeutic agent is a HBVpolymerase inhibitor. Examples of HBV DNA polymerase inhibitors include,but are not limited to, adefovir (HEPSERA®), emtricitabine (EMTRIVA®),tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide,tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate,tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovirdipivoxil fumarate, tenofovir octadecyloxyethyl ester, CMX-157,tenofovir exalidex, besifovir, entecavir (BARACLUDE®), entecavirmaleate, telbivudine (TYZEKA®), filocilovir, pradefovir, clevudine,ribavirin, lamivudine (EPIVIR-HBV®), phosphazide, famciclovir, fusolin,metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovirdisoproxil aspartate, tenofovir disoproxil orotate, and HS-10234. Insome embodiments, the additional therapeutic agent is a HBV capsidinhibitor.

In some embodiments, the additional therapeutic agent is an agent fortreatment of HIV. In some embodiments, the additional therapeutic agentis selected from the group consisting of HIV protease inhibitors, HIVintegrase inhibitors, entry inhibitors, HIV nucleoside reversetranscriptase inhibitors, HIV nonnucleoside reverse transcriptaseinhibitors, acyclic nucleoside phosphonate analogues, and combinationsthereof.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,HIV entry inhibitors, HIV maturation inhibitors, immunomodulators,immunotherapeutic agents, antibody-drug conjugates, gene modifiers, geneeditors (such as CRISPR/Cas9, zinc finger nucleases, homing nucleases,synthetic nucleases, TALENs), and cell therapies (such as chimericantigen receptor T-cell, CAR-T, and engineered T cell receptors, TCR-T,autologous T cell therapies).

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of combination drugs for HIV, other drugs fortreating HIV, HIV protease inhibitors, HIV reverse transcriptaseinhibitors, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIVmaturation inhibitors, latency reversing agents, capsid inhibitors,immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecificantibodies, and “antibody-like” therapeutic proteins, and combinationsthereof.

In some embodiments, the additional therapeutic agent is a HIVcombination drug. Examples of the HIV combination drugs include, but arenot limited to ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, andemtricitabine); BIKTARVY© (bictegravir, emtricitabine, and tenofoviralafenamide); COMPLERA© (EVIPLERA©; rilpivirine, tenofovir disoproxilfumarate, and emtricitabine); STRIBILD©(elvitegravir, cobicistat,tenofovir disoproxil fumarate, and emtricitabine); TRUVADA© (tenofovirdisoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofoviralafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide,emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide,emtricitabine, cobicistat, and elvitegravir); SYMTUZA© (darunavir,tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat);SYMFI™ (efavirenz, lamivudine, and tenofovir disoproxil fumarate);CIMDU™ (lamivudine and tenofovir disoproxil fumarate); tenofovir andlamivudine; tenofovir alafenamide and emtricitabine; tenofoviralafenamide hemifumarate and emtricitabine; tenofovir alafenamidehemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamidehemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR©(zidovudine and lamivudine; AZT+3TC); EPZICOM© (LIVEXA®; abacavirsulfate and lamivudine; ABC+3TC); KALETRA© (ALUVIA©; lopinavir andritonavir); TRIUMEQ© (dolutegravir, abacavir, and lamivudine); TRIZIVIR©(abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavirand cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfateand ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine;dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavirsulfate, and lamivudine; lamivudine, nevirapine, and zidovudine;raltegravir and lamivudine; doravirine, lamivudine, and tenofovirdisoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil;dapivirine+levonorgestrel, dolutegravir+lamivudine,dolutegravir+emtricitabine+tenofovir alafenamide,elsulfavirine+emtricitabine+tenofovir disoproxil,lamivudine+abacavir+zidovudine, lamivudine+abacavir,lamivudine+tenofovir disoproxil fumarate,lamivudine+zidovudine+nevirapine, lopinavir+ritonavir,lopinavir+ritonavir+abacavir+lamivudine,lopinavir+ritonavir+zidovudine+lamivudine, tenofovir+lamivudine, andtenofovir disoproxil fumarate+emtricitabine+rilpivirine hydrochloride,lopinavir, ritonavir, zidovudine and lamivudine.

In some embodiments, the additional therapeutic agent is a HIV proteaseinhibitor. For example, in some embodiments the additional therapeuticagent is selected from the group consisting of saquinavir, ritonavir,indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir,darunavir, tipranavir, cobicistat, ASC-09, AEBL-2, MK-8718, GS-9500,GS-1156, and combinations thereof. For example, in some embodiments theadditional therapeutic agent is selected from the group consisting ofsaquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir,atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat. In someembodiments, the additional therapeutic agent is selected from the groupconsisting of amprenavir, atazanavir, brecanavir, darunavir,fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate,lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir,saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169,BL-008, MK-8122, TMB-607, TMC-310911, and combinations thereof.

In some embodiments, the additional therapeutic agent is a HIV integraseinhibitor. For example, in some embodiment, the additional therapeuticagent is selected from the group consisting of raltegravir,elvitegravir, dolutegravir, abacavir, lamivudine, bictegravir andcombinations thereof. In some embodiment, the additional therapeuticagent is bictegravir. In some embodiments, the additional therapeuticagent is selected from a group consisting of bictegravir, elvitegravir,curcumin, derivatives of curcumin, chicoric acid, derivatives ofchicoric acid, 3,5-dicaffeoylquinic acid, derivatives of3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives ofaurintricarboxylic acid, caffeic acid phenethyl ester, derivatives ofcaffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin,quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351,bictegravir, AVX-15567, BMS-986197, cabotegravir (long-actinginjectable), diketo quinolin-4-1 derivatives, integrase-LEDGF inhibitor,ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710,NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid,T-169, VM-3500, cabotegravir, and combinations thereof.

In some embodiments, the additional therapeutic agent is a HIV entryinhibitor. For example, in some embodiments, the additional therapeuticagent is selected from the group consisting of enfuvirtide, maraviroc,and combinations thereof. Further examples of HIV entry inhibitorsinclude, but are not limited to, cenicriviroc, CCR5 inhibitors, gp41inhibitors, CD4 attachment inhibitors, DS-003 (BMS-599793), gpl20inhibitors, and CXCR4 inhibitors. Examples of CCR5 inhibitors includeaplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140),adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP(Haimipu). Examples of CXCR4 inhibitors include plerixafor, ALT-1188,N15 peptide, and vMIP (Haimipu).

In some embodiments, the additional therapeutic agent is a HIVnucleoside reverse transcriptase inhibitors. In some embodiments, theadditional therapeutic agent is a HIV nonnucleoside reversetranscriptase inhibitors. In some embodiments, the additionaltherapeutic agent is an acyclic nucleoside phosphonate analogue. In someembodiments, the additional therapeutic agent is a HIV capsid inhibitor.

In some embodiments, the additional therapeutic agent is a HIVnucleoside or nucleotide inhibitor of reverse transcriptase. Forexample, the additional therapeutic agent is selected from the groupconsisting of adefovir, adefovir dipivoxil, azvudine, emtricitabine,tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate,tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovirdisoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEXEC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine,apricitabine, censavudine, didanosine, elvucitabine, festinavir,fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine,OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir,lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafoviretalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500,KP-1461, and combinations thereof.

In some embodiments, the additional therapeutic agent is a HIVnon-nucleoside or non-nucleotide inhibitor of reverse transcriptase. Forexample, the additional agent is selected from the group consisting ofdapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz,etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA,ACC-007, AIC-292, KM-023, PC-1005, elsulfavirine rilp (VM-1500),combinations thereof.

In some embodiments, the additional therapeutic agents are selected fromATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine);COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, andemtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovirdisoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxilfumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamideand emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat;emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxilfumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate;TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir,abacavir sulfate, and lamivudine; raltegravir; raltegravir andlamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir andritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM®(LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavirsulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine;rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavirand cobicistat; darunavir and cobicistat; atazanavir; atazanavirsulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate andritonavir; darunavir; lamivudine; prolastin; fosamprenavir;fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavirmesylate; interferon; didanosine; stavudine; indinavir; indinavirsulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir;saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir;delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine andtenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovirdisoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine;abacavir; and abacavir sulfate.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of colistin, valrubicin, icatibant, bepotastine,epirubicin, epoprosetnol, vapreotide, aprepitant, caspofungin,perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir,penciclovir, prulifloxacin, bictegravir, nelfinavir, tegobuvi,nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, andzopiclone.

In some embodiments, the additional therapeutic agent is an inhibitor ofBruton tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, ID1, PSCTK1,XLA; NCBI Gene ID: 695). For example, in some embodiments, theadditional therapeutic agent is selected from the group consisting of(S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one,acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib(Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059),PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531,SHR-1459, DTRMWXHS-12, TAS-5315, AZD6738, calquence, danvatirsen, andcombinations thereof. In some embodiments, the additional therapeuticagent is selected from a group consisting of tirabrutinib, ibrutinib,acalabrutinib, and combinations thereof. In some embodiments, theadditional therapeutic agent is selected from a group consisting oftirabrutinib, ibrutinib, and combinations thereof. In some embodiments,the additional therapeutic agent is tyrphostin A9 (A9).

In some embodiments, the additional therapeutic agent is a KRASinhibitor. For example, in some embodiments, the additional therapeuticagent is selected from the group consisting of AMG-510, COTI-219,MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620(G12C), SML-8-73-1 (G12C), Compound 3144 (G12D), Kobe0065/2602 (RasGTP), RT11, MRTX-849 (G12C) and K-Ras(G12D)-selective inhibitorypeptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d(Ac-RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.

In some embodiments, the additional therapeutic agent is a proteasomeinhibitor. For example, in some embodiments, the additional therapeuticagent is selected from a group consisting of ixazomib, carfilzomib,marizomib, bortezomib, and combinations thereof. In some embodiments,the additional therapeutic agent is carfilzomib.

In some embodiments, the additional therapeutic agent is a vaccine. Forexample, in some embodiments, the additional therapeutic agent is a DNAvaccine, RNA vaccine, live-attenuated vaccine, therapeutic vaccine,prophylactic vaccine, protein based vaccine, or a combination thereof.In some embodiments, the additional therapeutic agent is mRNA-1273. Insome embodiments, the additional therapeutic agent is INO-4800 orINO-4700. In some embodiments, the additional therapeutic agent islive-attenuated RSV vaccine MEDI-559, human monoclonal antibody REGN2222against RSV, palivizumab, respiratory syncytial virus immune globulin,intravenous [RSV-IGIV], and combinations thereof. In some embodiments,the additional therapeutic agent is a HBV vaccine, for example pediarix,engerix-B, and recombivax HB. In some embodiments, the additionaltherapeutic agent is a VZV vaccine, for example zostavax and varivax. Insome embodiments, the additional therapeutic agent is a HPV vaccine, forexample cervarix, gardasil 9, and gardasil. In some embodiments, theadditional therapeutic agent is an influenza virus vaccine. For example,a (i) monovalent vaccine for influenza A (e.g., influenza A [H5N1] virusmonovalent vaccine and influenza A [H1N1] 2009 virus monovalentvaccines), (ii) trivalent vaccine for influenza A and B viruses (e.g.,Afluria, Agriflu, Fluad, Fluarix, Flublok, Flucelvax, FluLaval,Fluvirin, and Fluzone), and (iii) quadrivalent vaccine for influenza Aand B viruses (FluMist, Fluarix, Fluzone, and FluLaval). In someembodiments, the additional therapeutic agent is a human adenovirusvaccine (e.g., Adenovirus Type 4 and Type 7 Vaccine, Live, Oral). Insome embodiments, the additional therapeutic agent is a rotavirusvaccine (e.g., Rotarix for rotavirus serotype G1, G3, G4, or G9 andRotaTeq for rotavirus serotype G1, G2, G3, or G4). In some embodiments,the additional therapeutic agent is a hepatitis A virus vaccine (e.g.,Havrix and Vagta). In some embodiments, the additional therapeutic agentis poliovirus vaccines (e.g., Kinrix, Quadracel, and Ipol). In someembodiments, the additional therapeutic agent is a yellow fever virusvaccine (e.g., YF-Vax). In some embodiments, the additional therapeuticagent is a Japanese encephalitis virus vaccines (e.g., Ixiaro andJE-Vax). In some embodiments, the additional therapeutic agent is ameasles vaccine (e.g., M-M-R II and ProQuad). In some embodiments, theadditional therapeutic agent is a mumps vaccine (e.g., M-M-R II andProQuad). In some embodiments, the additional therapeutic agent is arubella vaccine (e.g., M-M-R II and ProQuad). In some embodiments, theadditional therapeutic agent is a varicella vaccine (e.g., ProQuad). Insome embodiments, the additional therapeutic agent is a rabies vaccine(e.g., Imovax and RabAvert). In some embodiments, the additionaltherapeutic agent is a variola virus (smallpox) vaccine (ACAM2000). Insome embodiments, the additional therapeutic agent is a and hepatitis Evirus (HEV) vaccine (e.g., HEV239). In some embodiments, the additionaltherapeutic agent is a 2019-nCov vaccine.

In some embodiments, the additional therapeutic agent is an antibody,for example a monoclonal antibody. For example, the additionaltherapeutic agent is an antibody against 2019-nCov selected from thegroup consisting of the Regeneron antibodies, the Wuxi Antibodies, theVir Biotechnology Antibodies, antibodies that target the SARS-CoV-2spike protein, antibodies that can neutralize SARS-CoV-2 (SARS-CoV-2neutralizing antibodies), and combinations thereof. In some embodiments,the additional therapeutic agent is anti-SARS-CoV antibody CR-3022. Insome embodiments, the additional therapeutic agent is aPD-1 antibody.

In some embodiments, the additional therapeutic agent is recombinantcytokine gene-derived protein injection.

In some embodiments, the additional therapeutic agent is a polymeraseinhibitor. In some embodiments, the additional therapeutic agent is aDNA polymerase inhibitor. For example, in some embodiments, theadditional therapeutic agent is cidofovir. In some embodiments, theadditional therapeutic agent is a RNA polymerase inhibitor. For example,in some embodiments, the additional therapeutic agent is selected fromthe group consisting of ribavirin, favipiravir, lamivudine, pimodivirand combination thereof.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of lopinavir, ritonavir, interferon-alpha-2b,ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, abidolhydrochloride, oseltamivir, litonavir, emtricitabine, tenofoviralafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinationsthereof.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of 6′-fluorinated aristeromycin analogues,acyclovir fleximer analogues, disulfiram, thiopurine analogues, ASC09F,GC376, GC813, phenylisoserine derivatives, neuroiminidase inhibitoranalogues, pyrithiobac derivatives, bananins and 5-hydroxychromonederivatives, SSYA10-001, griffithsin, HR2P-M1, HR2P-M2, P21S10,Dihydrotanshinone E-64-C and E-64-D, OC43-HR2P, MERS-5HB, 229E-HR1P,229E-HR2P, resveratrol, 1-thia-4-azaspiro[4.5]decan-3-one derivatives,gemcitabine hydrochloride, loperamide, recombinant interferons,cyclosporine A, alisporivir, imatinib mesylate, dasatinib, selumetinib,trametinib, rapamycin, saracatinib, chlorpromazine, triflupromazine,fluphenazine, thiethylperazine, promethazine, cyclophilin inhibitors,K11777, camostat, k22, teicoplanin derivatives, benzo-heterocyclic aminederivatives N30, mycophenolic acid, silvestrol, and combinationsthereof.

In some embodiments, the additional therapeutic agent is an antibody. Insome embodiments, the additional therapeutic agent is an antibody thatbinds to a coronavirus, for example an antibody that binds to SARS-CoVor MERS-CoV. In some embodiments, the additional therapeutic agent is aof 2019-nCoV virus antibody.

Compositions of the invention are also used in combination with otheractive ingredients. For the treatment of 2019-nCoV virus infections,preferably, the other active therapeutic agent is active againstcoronavirus infections, for example 2019-nCoV virus infections. Thecompounds and compositions of the present invention are also intendedfor use with general care provided patients with 2019-nCoV viralinfections, including parenteral fluids (including dextrose saline andRinger's lactate) and nutrition, antibiotic (including metronidazole andcephalosporin antibiotics, such as ceftriaxone and cefuroxime) and/orantifungal prophylaxis, fever and pain medication, antiemetic (such asmetoclopramide) and/or antidiarrheal agents, vitamin and mineralsupplements (including Vitamin K and zinc sulfate), anti-inflammatoryagents (such as ibuprofen or steroids), corticosteroids such asmethylprednisolone, immunomodulatory medications (e.g., interferon),other small molecule or biologics antiviral agents targeting 2019-nCoV(such as but not limited to lopinavir/ritonavir, EIDD-1931, favipiravir,ribavirine, neutralizing antibodies, etc.), vaccines, pain medications,and medications for other common diseases in the patient population,such anti-malarial agents (including artemether andartesunate-lumefantrine combination therapy), typhoid (includingquinolone antibiotics, such as ciprofloxacin, macrolide antibiotics,such as azithromycin, cephalosporin antibiotics, such as ceftriaxone, oraminopenicillins, such as ampicillin), or shigellosis. In someembodiments, the additional therapeutic agent isdihydroartemisinin/piperaquine. In some embodiments, the additionaltherapeutic agent is EIDD-2801 (MH-4482, Molnupiravir).

In some embodiments, the additional therapeutic agent is animmunomodulator. Examples of immune-based therapies include toll-likereceptors modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7,tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell deathprotein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-L1)modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil(hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alfa;interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa;interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its esterderivative mycophenolate mofetil (MMF); ribavirin; polymerpolyethyleneimine (PEI); gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559;CYT-107, interleukin-15/Fc fusion protein, AM-0015, ALT-803, NIZ-985,NKTR-255, NKTR-262, NKTR-214, normferon, peginterferon alfa-2a,peginterferon alfa-2b, recombinant interleukin-15, Xmab-24306, RPI-MN,STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, andIR-103. In some embodiments, the additional therapeutic agent isfingolimod, leflunomide, or a combination thereof. In some embodiments,the additional therapeutic agent is thalidomide.

In some embodiments, the additional therapeutic agent is an IL-6inhibitor, for example tocilizumab, sarilumab, or a combination thereof.

In some embodiments, the additional therapeutic agent is an anti-TNFinhibitor. For example, the additional therapeutic agent is adalimumab,etanercept, golimumab, infliximab, or a combination thereof.

In some embodiments, the additional therapeutic agent is a JAKinhibitor, for example the additional therapeutic agent is baricitinib,filgotinib, olumiant, or a combination thereof.

In some embodiments, the additional therapeutic agent is an inflammationinhibitor, for example pirfenidone.

In some embodiments, the additional therapeutic agent is an antibioticfor secondary bacterial pneumonia. For example, the additionaltherapeutic agent is macrolide antibiotics (e.g., azithromycin,clarithromycin, and Mycoplasma pneumoniae), fluoroquinolones (e.g.,ciprofloxacin and levofloxacin), tetracyclines (e.g., doxycycline andtetracycline), or a combination thereof.

In some embodiments, the compounds disclosed herein are used incombination with pneumonia standard of care (see e.g., PediatricCommunity Pneumonia Guidelines, CID 2011:53 (1 October)). Treatment forpneumonia generally involves curing the infection and preventingcomplications. Specific treatment will depend on several factors,including the type and severity of pneumonia, age and overall health ofthe individuals. The options include: (i) antibiotics, (ii) coughmedicine, and (iii) fever reducers/pain relievers (for e.g., aspirin,ibuprofen (Advil, Motrin IB, others) and acetaminophen (Tylenol,others)). In some embodiments, the additional therapeutic agent isbromhexine anti-cough.

In some embodiments, the compounds disclosed herein are used incombination with immunoglobulin from cured COVID-19 patients. In someembodiments, the compounds disclosed herein are used in combination withplasma transfusion. In some embodiments, the compounds disclosed hereinare used in combination with stem cells.

In some embodiments, the additional therapeutic agent is an TLR agonist.Examples of TLR agonists include, but are not limited to, vesatolimod(GS-9620), GS-986, IR-103, lefitolimod, tilsotolimod, rintatolimod,DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091,GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, telratolimod,and RO-7020531.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of bortezomid, flurazepam, ponatinib, sorafenib,paramethasone, clocortolone, flucloxacillin, sertindole, clevidipine,atorvastatin, cinolazepam, clofazimine, fosaprepitant, and combinationsthereof.

In some embodiments, the additional therapeutic agent is carrimycin,suramin, triazavirin, dipyridamole, bevacizumab, meplazumab, GD31(rhizobium), NLRP inflammasome inhibitor, or α-ketoamine. In someembodiments, the additional therapeutic agent is recombinant humanangiotensin-converting enzyme 2 (rhACE2). In some embodiments, theadditional therapeutic agent is viral macrophage inflammatory protein(vMIP).

In some embodiments, the additional therapeutic agent is ananti-viroporin therapeutic. For example, the additional therapeuticagent is BIT-314 or BIT-225. In some embodiments, the additionaltherapeutic agent is coronavirus E protein inhibitor. For example, theadditional therapeutic agent is BIT-009. Further examples of additionaltherapeutic agents include those described in WO-2004112687,WO-2006135978, WO-2018145148, and WO-2009018609.

In some embodiments, the additional therapeutic or prophylactic agent ismolnupiravir, oseltamivir, nirmatrelvir, or ritonavir. In someembodiments, the additional therapeutic or prophylactic agent isritonavir or cobicistat.

It is possible to combine any compound of the invention with one of moreadditional active therapeutic agents. For example, the compounddescribed herein can be combined with one, two, three, four, five, ormore additional active therapeutic agents.

It is also possible to combine any compound of the invention with one ormore additional active therapeutic agents in a unitary dosage form forsimultaneous or sequential administration to a patient. The combinationtherapy may be administered as a simultaneous or sequential regimen.When administered sequentially, the combination may be administered intwo or more administrations.

Co-administration of a compound of the invention with one or more otheractive therapeutic agents generally refers to simultaneous or sequentialadministration of a compound of the invention and one or more otheractive therapeutic agents, such that therapeutically effective amountsof the compound of the invention and one or more other activetherapeutic agents are both present in the body of the patient.

Co-administration includes administration of unit dosages of thecompounds of the invention before or after administration of unitdosages of one or more other active therapeutic agents, for example,administration of the compounds of the invention within seconds,minutes, or hours of the administration of one or more other activetherapeutic agents. For example, a unit dose of a compound of theinvention can be administered first, followed within seconds or minutesby administration of a unit dose of one or more other active therapeuticagents. Alternatively, a unit dose of one or more other therapeuticagents can be administered first, followed by administration of a unitdose of a compound of the invention within seconds or minutes. In somecases, it may be desirable to administer a unit dose of a compound ofthe invention first, followed, after a period of hours (e.g., 1-12hours), by administration of a unit dose of one or more other activetherapeutic agents. In other cases, it may be desirable to administer aunit dose of one or more other active therapeutic agents first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound of the invention.

The combination therapy may provide “synergy” and “synergistic”, i.e.,the effect achieved when the active ingredients used together is greaterthan the sum of the effects that results from using the compoundsseparately. A synergistic effect may be attained when the activeingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined formulation; (2) delivered by alternationor in parallel as separate formulations; or (3) by some other regimen.When delivered in alternation therapy, a synergistic effect may beattained when the compounds are administered or delivered sequentially,e.g., in separate tablets, pills or capsules, or by different injectionsin separate syringes. In general, during alternation therapy, aneffective dosage of each active ingredient is administered sequentially,i.e., serially, whereas in combination therapy, effective dosages of twoor more active ingredients are administered together. A synergisticanti-viral effect denotes an antiviral effect, which is greater than thepredicted purely additive effects of the individual compounds of thecombination.

1. Combination Therapy for the Treatment of Pneumoviridae

The compounds provided herein are also used in combination with otheractive therapeutic agents. For the treatment of Pneumoviridae virusinfections, preferably, the other active therapeutic agent is activeagainst Pneumoviridae virus infections, particularly respiratorysyncytial virus infections and/or metapneumovirus infections.Non-limiting examples of these other active therapeutic agents activeagainst RSV are ribavirin, palivizumab, motavizumab, RSV-IGIV(RespiGam©), MEDI-557, A-60444 (also known as RSV604), MDT-637,BMS-433771, ALN-RSV0, ALX-0171 and mixtures thereof. Other non-limitingexamples of other active therapeutic agents active against respiratorysyncytial virus infections include respiratory syncytial virus protein Finhibitors, such as AK-0529; RV-521, ALX-0171, JNJ-53718678, BTA-585,and presatovir; RNA polymerase inhibitors, such as lumicitabine andALS-8112; anti-RSV G protein antibodies, such as anti-G-protein mAb;viral replication inhibitors, such as nitazoxanide.

In some embodiments, the other active therapeutic agent may be a vaccinefor the treatment or prevention of RSV, including but not limited toMVA-BN RSV, RSV-F, MEDI-8897, JNJ-64400141, DPX-RSV, SynGEM,GSK-3389245A, GSK-300389-1A, RSV-MEDI deltaM2-2 vaccine,VRC-RSVRGP084-00VP, Ad35-RSV-FA2, Ad26-RSV-FA2, and RSV fusionglycoprotein subunit vaccine.

Non-limiting examples of other active therapeutic agents active againstmetapneumovirus infections include sialidase modulators such as DAS-181;RNA polymerase inhibitors, such as ALS-8112; and antibodies for thetreatment of Metapneumovirus infections, such as EV-046113.

In some embodiments, the other active therapeutic agent may be a vaccinefor the treatment or prevention of metapneumovirus infections, includingbut not limited to mRNA-1653 and rHMPV-Pa vaccine.

2. Combination Therapy for the Treatment of Picornaviridae

The compounds provided herein are also used in combination with otheractive therapeutic agents. For the treatment of Picornaviridae virusinfections, preferably, the other active therapeutic agent is activeagainst Picornaviridae virus infections, particularly Enterovirusinfections. Non-limiting examples of these other active therapeuticagents are capsid binding inhibitors such as pleconaril, BTA-798(vapendavir) and other compounds disclosed by Wu, et al. (U.S. Pat. No.7,078,403) and Watson (U.S. Pat. No. 7,166,604); fusion sialidaseprotein such as DAS-181; a capsid protein VP1 inhibitor such as VVX-003and AZN-001; a viral protease inhibitor such as CW-33; aphosphatidylinositol 4 kinase beta inhibitor such as GSK-480 andGSK-533; anti-EV71 antibody.

In some embodiments, the other active therapeutic agent may be a vaccinefor the treatment or prevention of Picornaviridae virus infections,including but not limited to EV71 vaccines, TAK-021, and EV-D68adenovector-based vaccine.

3. Combination Therapy for Respiratory Infections

Many of the infections of the Pneumoviridae, Picornaviridae, andCoronaviridae viruses are respiratory infections. Therefore, additionalactive therapeutics used to treat respiratory symptoms and sequelae ofinfection may be used in combination with the compounds provided herein.The additional agents are preferably administered orally or by directinhalation. For example, other preferred additional therapeutic agentsin combination with the compounds provided herein for the treatment ofviral respiratory infections include, but are not limited to,bronchodilators and corticosteroids.

Glucocorticoids

Glucocorticoids, which were first introduced as an asthma therapy in1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the mostpotent and consistently effective therapy for this disease, althoughtheir mechanism of action is not yet fully understood (Morris, J.Allergy Clin. Immunol., 75 (1 Pt) 1-13, 1985). Unfortunately, oralglucocorticoid therapies are associated with profound undesirable sideeffects such as truncal obesity, hypertension, glaucoma, glucoseintolerance, acceleration of cataract formation, bone mineral loss, andpsychological effects, all of which limit their use as long-termtherapeutic agents (Goodman and Gilman, 10th edition, 2001). A solutionto systemic side effects is to deliver steroid drugs directly to thesite of inflammation. Inhaled corticosteroids (ICS) have been developedto mitigate the severe adverse effects of oral steroids. Non-limitingexamples of corticosteroids that may be used in combinations with thecompounds provided herein are dexamethasone, dexamethasone sodiumphosphate, fluorometholone, fluorometholone acetate, loteprednol,loteprednol etabonate, hydrocortisone, prednisolone, fludrocortisones,triamcinolone, triamcinolone acetonide, betamethasone, beclomethasonediproprionate, methylprednisolone, fluocinolone, fluocinolone acetonide,flunisolide, fluocortin-21-butylate, flumethasone, flumetasone pivalate,budesonide, halobetasol propionate, mometasone furoate, fluticasone,AZD-7594, ciclesonide; or a pharmaceutically acceptable salts thereof.

Anti-Inflammatory Agents

Other anti-inflammatory agents working through anti-inflammatory cascademechanisms are also useful as additional therapeutic agents incombination with the compounds provided herein for the treatment ofviral respiratory infections. Applying “anti-inflammatory signaltransduction modulators” (referred to in this text as AIS™), likephosphodiesterase inhibitors (e.g., PDE-4, PDE-5, or PDE-7 specific),transcription factor inhibitors (e.g., blocking NFκB through IKKinhibition), or kinase inhibitors (e.g., blocking P38 MAP, JNK, PI3K,EGFR or Syk) is a logical approach to switching off inflammation asthese small molecules target a limited number of common intracellularpathways—those signal transduction pathways that are critical points forthe anti-inflammatory therapeutic intervention (see review by P. J.Barnes, 2006). These non-limiting additional therapeutic agents include:5-(2,4-Difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid(2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797);3-Cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluoromethoxy-benzamide(PDE-4 inhibitor Roflumilast);4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4inhibitor CDP-840);N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide(PDE-4 inhibitor Oglemilast);N-(3,5-Dichloro-pyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxo-acetamide(PDE-4 inhibitor AWD 12-281);8-Methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid(3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591);4-[5-(4-Fluorophenyl)-2-(4-methanesulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine(P38 inhibitor SB-203850);4-[4-(4-Fluoro-phenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-but-3-yn-1-ol(P38 inhibitor RWJ-67657);4-Cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid2-diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of Cilomilast,PDE-4 inhibitor);(3-Chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine(Gefitinib, EGFR inhibitor); and4-(4-Methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide(Imatinib, EGFR inhibitor).

β2-Adrenoreceptor Agonist Bronchodilators

Combinations comprising inhaled β2-adrenoreceptor agonistbronchodilators such as formoterol, albuterol or salmeterol with thecompounds provided herein are also suitable, but non-limiting,combinations useful for the treatment of respiratory viral infections.

Combinations of inhaled β2-adrenoreceptor agonist bronchodilators suchas formoterol or salmeterol with ICS's are also used to treat both thebronchoconstriction and the inflammation (Symbicort® and Advair®,respectively). The combinations comprising these ICS andβ2-adrenoreceptor agonist combinations along with the compounds providedherein are also suitable, but non-limiting, combinations useful for thetreatment of respiratory viral infections.

Other examples of Beta 2 adrenoceptor agonists are bedoradrine,vilanterol, indacaterol, olodaterol, tulobuterol, formoterol,abediterol, salbutamol, arformoterol, levalbuterol, fenoterol, andTD-5471.

Anticholinergics

For the treatment or prophylaxis of pulmonary broncho-constriction,anticholinergics are of potential use and, therefore, useful as anadditional therapeutic agent in combination with the compounds providedherein for the treatment of viral respiratory infections. Theseanticholinergics include, but are not limited to, antagonists of themuscarinic receptor (particularly of the M3 subtype) which have showntherapeutic efficacy in man for the control of cholinergic tone in COPD(Witek, 1999);1-{4-Hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)-propionyl]-pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylicacid (1-methyl-piperidin-4-ylmethyl)-amide;3-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-8-isopropyl-8-methyl-8-azonia-bicyclo[3.2.1]octane(Ipratropium-N,N-diethylglycinate);1-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid1-aza-bicyclo[2.2.2]oct-3-yl ester (Solifenacin);2-Hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid1-aza-bicyclo[2.2.2]oct-3-yl ester (Revatropate);2-{1-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-acetamide(Darifenacin); 4-Azepan-1-yl-2,2-diphenyl-butyramide (Buzepide);7-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane(Oxitropium-N,N-diethylglycinate);7-[2-(2-Diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane(Tiotropium-N,N-diethylglycinate); Dimethylamino-acetic acid2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester(Tolterodine-N,N-dimethylglycinate);3-[4,4-Bis-(4-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl-ethyl)-pyrrolidinium;1-[1-(3-Fluoro-benzyl)-piperidin-4-yl]-4,4-bis-(4-fluoro-phenyl)-imidazolidin-2-one;1-Cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2]oct-3-yl)-1-phenyl-prop-2-yn-1-ol;3-[2-(2-Diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane(Aclidinium-N,N-diethylglycinate); or(2-Diethylamino-acetoxy)-di-thiophen-2-yl-acetic acid1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester; revefenacin,glycopyrronium bromide, umeclidinium bromide, tiotropium bromide,aclidinium bromide, bencycloquidium bromide.

Mucolytic Agents

The compounds provided herein may also be combined with mucolytic agentsto treat both the infection and symptoms of respiratory infections. Anon-limiting example of a mucolytic agent is ambroxol. Similarly, thecompounds may be combined with expectorants to treat both the infectionand symptoms of respiratory infections. A non-limiting example of anexpectorant is guaifenesin.

Nebulized hypertonic saline is used to improve immediate and long-termclearance of small airways in patients with lung diseases (Kuzik, J.Pediatrics 2007, 266). Thus, the compounds provided herein may also becombined with nebulized hypertonic saline particularly when the virusinfection is complicated with bronchiolitis. The combination of thecompound provided herein with hypertonic saline may also comprise any ofthe additional agents discussed above. In one embodiment, nebulizedabout 3% hypertonic saline is used.

4. Combination Therapy for the Treatment of Flaviviridae VirusInfections

The compounds and compositions provided herein are also used incombination with other active therapeutic agents. For the treatment ofFlaviviridae virus infections, preferably, the other active therapeuticagent is active against Flaviviridae virus infections.

For treatment of the dengue virus infection, non-limiting examples ofthe other active therapeutic agents are host cell factor modulators,such as GBV-006; fenretinide ABX-220, BRM-211; alpha-glucosidase 1inhibitors, such as celgosivir; platelet activating factor receptor(PAFR) antagonists, such as modipafant; cadherin-5/Factor Ia modulators,such as FX-06; NS4B inhibitors, such as JNJ-8359; viral RNA splicingmodulators, such as ABX-202; a NS5 polymerase inhibitor; a NS3 proteaseinhibitor; and a TLR modulator.

In some embodiments, the other active therapeutic agent may be a vaccinefor the treatment or prevention of dengue, including but not limited toTetraVax-DV, Dengvaxia®, DPIV-001, TAK-003, live attenuated denguevaccine, tetravalent dengue fever vaccine, tetravalent DNA vaccine,rDEN2delta30-7169; and DENV-1 PIV.

5. Combination Therapy for the Treatment of Filoviridae Virus Infections

The compounds provided herein are also used in combination with otheractive therapeutic agents. For the treatment of Filoviridae virusinfections, preferably, the other active therapeutic agent is activeagainst Filoviridae virus infections, particularly Marburg virus, Ebolavirus and Cueva virus infections. Non-limiting examples of these otheractive therapeutic agents are: ribavirin, amiodarone, dronedarone,verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol),TKM-Ebola, T-705 monophosphate, T-705 diphosphate, T-705 triphosphate,FGI-106(1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h]quinolone-1,7-diamine),rNAPc2, OS-2966, brincidofovir, remdesivir; RNA polymerase inhibitors,such as galidesivir, favipiravir (also known as T-705 or Avigan), JK-05;host cell factor modulators, such as GMV-006; cadherin-5/factor Iamodulators, such as FX-06; and antibodies for the treatment of Ebola,such as REGN-3470-3471-3479 and ZMapp.

Other non-limiting active therapeutic agents active against Ebolainclude an alpha-glucosidase 1 inhibitor, a cathepsin B inhibitor, aCD29 antagonist, a dendritic ICAM-3 grabbing nonintegrin 1 inhibitor, anestrogen receptor antagonist, a factor VII antagonist HLA class IIantigen modulator, a host cell factor modulator, a Interferon alphaligand, a neutral alpha glucosidase AB inhibitor, a niemann-Pick C1protein inhibitor, a nucleoprotein inhibitor, a polymerase cofactor VP35inhibitor, a Serine protease inhibitor, a tissue factor inhibitor, aTLR-3 agonist, a viral envelope glycoprotein inhibitor, and an Ebolavirus entry inhibitors (NPC1 inhibitors).

In some embodiments, the other active therapeutic agent may be a vaccinefor the treatment or prevention of Ebola, including but not limited toVRC-EBOADC076-00-VP, adenovirus-based Ebola vaccine, rVSV-EBOV,rVSVN4CT1-EBOVGP, MVA-BN Filo+Ad26-ZEBOV regimen, INO-4212,VRC-EBODNA023-00-VP, VRC-EBOADC069-00-VP, GamEvac-combi vaccine, SRC VBVector, HPIV3/EboGP vaccine, MVA-EBOZ, Ebola recombinant glycoproteinvaccine, Vaxart adenovirus vector 5-based Ebola vaccine, FiloVaxvaccine, GOVX-E301, and GOVX-E302.

The compounds provided herein may also be used in combination withphosphoramidate morpholino oligomers (PMOs), which are syntheticantisense oligonucleotide analogs designed to interfere withtranslational processes by forming base-pair duplexes with specific RNAsequences. Examples of PMOs include but are not limited to AVI-7287,AVI-7288, AVI-7537, AVI-7539, AVI-6002, and AVI-6003.

The compounds provided herein are also intended for use with generalcare provided to patients with Filoviridae viral infections, includingparenteral fluids (including dextrose saline and Ringer's lactate) andnutrition, antibiotic (including metronidazole and cephalosporinantibiotics, such as ceftriaxone and cefuroxime) and/or antifungalprophylaxis, fever and pain medication, antiemetic (such asmetoclopramide) and/or antidiarrheal agents, vitamin and mineralsupplements (including Vitamin K and zinc sulfate), anti-inflammatoryagents (such as ibuprofen), pain medications, and medications for othercommon diseases in the patient population, such anti-malarial agents(including artemether and artesunate-lumefantrine combination therapy),typhoid (including quinolone antibiotics, such as ciprofloxacin,macrolide antibiotics, such as azithromycin, cephalosporin antibiotics,such as ceftriaxone, or aminopenicillins, such as ampicillin), orshigellosis.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposesand are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters, which can be changed or modified to yield essentially thesame results.

6. Combination Therapy for the Treatment of Coronaviridae VirusInfections

In some embodiments, the additional therapeutic agent a2,5-Oligoadenylate synthetase stimulator, 5-HT 2a receptor antagonist,5-Lipoxygenase inhibitor, ABL family tyrosine kinase inhibitor, Abltyrosine kinase inhibitor, Acetaldehyde dehydrogenase inhibitor, AcetylCoA carboxylase inhibitor, Actin antagonist, Actin modulator,Activity-dependent neuroprotector modulator, Adenosine A3 receptoragonist, Adrenergic receptor antagonist, Adrenomedullin ligand,Adrenomedullin ligand inhibitor, Advanced glycosylation product receptorantagonist, Advanced glycosylation product receptor modulator, AKTprotein kinase inhibitor, Alanine proline rich secreted proteinstimulator, Aldose reductase inhibitor, Alkaline phosphatase stimulator,Alpha 2 adrenoceptor antagonist, Alpha 2B adrenoceptor agonist, AMPactivated protein kinase stimulator, AMPA receptor modulator, Amyloidprotein deposition inhibitor, Androgen receptor antagonist, AngiotensinII AT-1 receptor antagonist, Angiotensin II AT-2 receptor agonist,Angiotensin II receptor modulator, Angiotensin converting enzyme 2inhibitor, Angiotensin converting enzyme 2 modulator, Angiotensinconverting enzyme 2 stimulator, Angiotensin receptor modulator, AnnexinA5 stimulator, Anoctamin 1 inhibitor, Anti-coagulant, Anti-histamine,Anti-hypoxic, Anti-thrombotic, AP1 transcription factor modulator,Apelin receptor agonist, APOA1 gene stimulator, Apolipoprotein A1agonist, Apolipoprotein B antagonist, Apolipoprotein B modulator,Apolipoprotein C3 antagonist, Aryl hydrocarbon receptor agonist, Arylhydrocarbon receptor antagonist, ATP binding cassette transporter B5modulator, Axl tyrosine kinase receptor inhibitor, Bactericidalpermeability protein inhibitor, Basigin inhibitor, Basigin modulator,BCL2 gene inhibitor, BCL2L11 gene stimulator, Bcr protein inhibitor,Beta 1 adrenoceptor modulator, Beta 2 adrenoceptor agonist, Betaadrenoceptor agonist, Beta-arrestin stimulator, Blood clottingmodulator, BMP10 gene inhibitor, BMP15 gene inhibitor, Bonemorphogenetic protein-10 ligand inhibitor, Bone morphogenetic protein-15ligand inhibitor, Bradykinin B2 receptor antagonist, Brain derivedneurotrophic factor ligand, Bromodomain containing protein 2 inhibitor,Bromodomain containing protein 4 inhibitor, Btk tyrosine kinaseinhibitor, C-reactive protein modulator, Ca2+ release activated Ca2+channel 1 inhibitor, Cadherin-5 modulator, Calcium activated chloridechannel inhibitor, Calcium channel modulator, Calpain-I inhibitor,Calpain-II inhibitor, Calpain-IX inhibitor, Cannabinoid CB2 receptoragonist, Cannabinoid receptor modulator, Casein kinase II inhibitor,CASP8-FADD-like regulator inhibitor, Caspase inhibitor, Catalasestimulator, CCL26 gene inhibitor, CCR2 chemokine antagonist, CCR5chemokine antagonist, CD11a agonist, CD122 agonist, CD3 antagonist, CD4agonist, CD40 ligand, CD40 ligand modulator, CD40 ligand receptoragonist, CD40 ligand receptor modulator, CD49d agonist, CD70 antigenmodulator, CD73 agonist, CD73 antagonist, CD95 antagonist, CFTRinhibitor, CGRP receptor antagonist, Chemokine receptor-like 1 agonist,Chloride channel inhibitor, Chloride channel modulator, Choleraenterotoxin subunit B inhibitor, Cholesterol ester transfer proteininhibitor, Collagen modulator, Complement CIs subcomponent inhibitor,Complement C3 inhibitor, Complement C5 factor inhibitor, Complement C5afactor inhibitor, Complement Factor H stimulator, Complement cascadeinhibitor, Complement factor C₂ inhibitor, Complement factor Dinhibitor, Connective tissue growth factor ligand inhibitor, Coronavirusnucleoprotein modulator, Coronavirus small envelope protein modulator,Coronavirus spike glycoprotein inhibitor, Coronavirus spike glycoproteinmodulator, COVID19 envelope small membrane protein modulator, COVID19non structural protein 8 modulator, COVID19 nucleoprotein modulator,COVID19 Protein 3a inhibitor, COVID19 replicase polyprotein 1ainhibitor, COVID19 replicase polyprotein 1a modulator, COVID19 replicasepolyprotein lab inhibitor, COVID19 replicase polyprotein lab modulator,COVID19 Spike glycoprotein inhibitor, COVID19 Spike glycoproteinmodulator, COVID19 structural glycoprotein modulator, CRF-2 receptoragonist, CSF-1 agonist, CSF-1 antagonist, CX3CR1 chemokine antagonist,CXC10 chemokine ligand inhibitor, CXC5 chemokine ligand inhibitor, CXCL1gene modulator, CXCL2 gene modulator, CXCL3 gene modulator, CXCR1chemokine antagonist, CXCR2 chemokine antagonist, CXCR4 chemokineantagonist, Cyclin D1 inhibitor, Cyclin E inhibitor, Cyclin-dependentkinase-1 inhibitor, Cyclin-dependent kinase-2 inhibitor,Cyclin-dependent kinase-5 inhibitor, Cyclin-dependent kinase-7inhibitor, Cyclin-dependent kinase-9 inhibitor, Cyclooxygenase 2inhibitor, Cyclooxygenase inhibitor, Cyclophilin inhibitor, Cysteineprotease inhibitor, Cytochrome P450 3A4 inhibitor, Cytokine receptorantagonist, Cytotoxic T lymphocyte protein gene modulator, CytotoxicT-lymphocyte protein-4 inhibitor, Cytotoxic T-lymphocyte protein-4stimulator, DDX3 inhibitor, Dehydrogenase inhibitor, Dehydropeptidase-1modulator, Deoxyribonuclease I stimulator, Deoxyribonuclease gammastimulator, Deoxyribonuclease stimulator, Dihydroceramide delta 4desaturase inhibitor, Dihydroorotate dehydrogenase inhibitor, Dipeptidylpeptidase I inhibitor, Dipeptidyl peptidase III inhibitor, Diuretic, DNAbinding protein inhibitor, DNA methyltransferase inhibitor, Dopaminetransporter inhibitor, E selectin antagonist, Ecto NOX disulfide thiolexchanger 2 inhibitor, EGFR gene inhibitor, Elongation factor 1 alpha 2modulator, Endoplasmin modulator, Endoribonuclease DICER modulator,Endothelin ET-A receptor antagonist, Epidermal growth factor receptorantagonist, E-selectin antagonist, Estrogen receptor beta agonist,Estrogen receptor modulator, Eukaryotic initiation factor 4A-Iinhibitor, Exo-alpha sialidase modulator, Exportin 1 inhibitor, FactorIa modulator, Factor IIa modulator, Factor VII antagonist, Factor Xaantagonist, Factor XIa antagonist, FGF receptor antagonist, FGF-1ligand, FGF-1 ligand inhibitor, FGF-2 ligand inhibitor, FGF1 receptorantagonist, FGF2 receptor antagonist, FGF3 receptor antagonist, Flt3tyrosine kinase inhibitor, Fractalkine ligand inhibitor, Free fatty acidreceptor 2 agonist, Free fatty acid receptor 3 agonist, furininhibitors, Fyn tyrosine kinase inhibitor, FYVE finger phosphoinositidekinase inhibitor, G-protein coupled bile acid receptor 1 agonist, GABA Areceptor modulator, Galectin-3 inhibitor, Gamma-secretase inhibitor, GDFagonist, Gelsolin stimulator, Glial cell neurotrophic factor ligand,Glucocorticoid receptor agonist, Glutathione peroxidase stimulator,GM-CSF ligand inhibitor, GM-CSF receptor agonist, GM-CSF receptormodulator, Griffithsin modulator, Growth regulated protein alpha ligandinhibitor, Grp78 calcium binding protein inhibitor, Heat shock proteinHSP90 alpha inhibitor, Heat shock protein HSP90 beta inhibitor, Heatshock protein inhibitor, Heat shock protein stimulator, Hemagglutininmodulator, Hemoglobin modulator, Hemolysin alpha inhibitor, Heparanaseinhibitor, Heparin agonist, Hepatitis B structural protein inhibitor,Hepatitis C virus NS5B polymerase inhibitor, HIF prolyl hydroxylaseinhibitor, HIF prolyl hydroxylase-2 inhibitor, High mobility groupprotein B1 inhibitor, Histamine H1 receptor antagonist, Histamine H2receptor antagonist, Histone deacetylase-6 inhibitor, Histone inhibitor,HIV protease inhibitor, HIV-1 gp120 protein inhibitor, HIV-1 proteaseinhibitor, HIV-1 reverse transcriptase inhibitor, HLA class I antigenmodulator, HLA class II antigen modulator, Host cell factor modulator,Hsp 90 inhibitor, Human papillomavirus E6 protein modulator, Humanpapillomavirus E7 protein modulator, Hypoxia inducible factor inhibitorgene inhibitor, Hypoxia inducible factor-2 alpha modulator, I-kappa Bkinase inhibitor, I-kappa B kinase modulator, ICAM-1 stimulator, IgGreceptor FcRn large subunit p51 modulator, IL-12 receptor antagonist,IL-15 receptor agonist, IL-15 receptor modulator, IL-17 antagonist,IL-18 receptor accessory protein antagonist, IL-2 receptor agonist,IL-22 agonist, IL-23 antagonist, IL-6 receptor agonist, IL-6 receptorantagonist, IL-6 receptor modulator, IL-7 receptor agonist, IL-8receptor antagonist, IL12 gene stimulator, IL8 gene modulator,Immunoglobulin G modulator, Immunoglobulin G1 agonist, Immunoglobulin G1modulator, Immunoglobulin agonist, Immunoglobulin gamma Fc receptor Imodulator, Immunoglobulin kappa modulator, Inosine monophosphatedehydrogenase inhibitor, Insulin sensitizer, Integrin agonist, Integrinalpha-4/beta-7 antagonist, Integrin alpha-V/beta-1 antagonist, Integrinalpha-V/beta-6 antagonist, Interferon agonist, Interferon alpha 14ligand, Interferon alpha 2 ligand, Interferon alpha 2 ligand modulator,Interferon alpha ligand, Interferon alpha ligand inhibitor, Interferonalpha ligand modulator, Interferon beta ligand, Interferon gamma ligandinhibitor, Interferon gamma receptor agonist, Interferon gamma receptorantagonist, Interferon receptor modulator, Interferon type I receptoragonist, Interleukin 17A ligand inhibitor, Interleukin 17F ligandinhibitor, Interleukin 18 ligand inhibitor, Interleukin 22 ligand,Interleukin-1 beta ligand inhibitor, Interleukin-1 beta ligandmodulator, Interleukin-1 ligand inhibitor, Interleukin-2 ligand,Interleukin-29 ligand, Interleukin-6 ligand inhibitor, Interleukin-7ligand, Interleukin-8 ligand inhibitor, IRAK-4 protein kinase inhibitor,JAK tyrosine kinase inhibitor, Jak1 tyrosine kinase inhibitor, Jak2tyrosine kinase inhibitor, Jak3 tyrosine kinase inhibitor, Jun Nterminal kinase inhibitor, Jun N terminal kinase modulator, Kallikreinmodulator, Kelch like ECH associated protein 1 modulator, Kit tyrosinekinase inhibitor, KLKB1 gene inhibitor, Lactoferrin stimulator,Lanosterol-14 demethylase inhibitor, Lck tyrosine kinase inhibitor,Leukocyte Ig like receptor A4 modulator, Leukocyte elastase inhibitor,Leukotriene BLT receptor antagonist, Leukotriene D4 antagonist,Leukotriene receptor antagonist, Listeriolysin stimulator, Liver Xreceptor antagonist, Low molecular weight heparin, Lung surfactantassociated protein B stimulator, Lung surfactant associated protein Dmodulator, Lyn tyrosine kinase inhibitor, Lyn tyrosine kinasestimulator, Lysine specific histone demethylase 1 inhibitor, Macrophagemigration inhibitory factor inhibitor, Mannan-binding lectin serineprotease inhibitor, Mannan-binding lectin serine protease-2 inhibitor,MAO B inhibitor, MAP kinase inhibitor, MAPK gene modulator, Matrixmetalloprotease modulator, Maxi K potassium channel inhibitor, MCL1 geneinhibitor, MEK protein kinase inhibitor, MEK-1 protein kinase inhibitor,Melanocortin MC1 receptor agonist, Melanocortin MC3 receptor agonist,Metalloprotease-12 inhibitor, METTL3 gene inhibitor, Moesin inhibitor,Moesin modulator, Monocyte chemotactic protein 1 ligand inhibitor,Monocyte differentiation antigen CD14 inhibitor, mRNA cap guanine N7methyltransferase modulator, mTOR complex 1 inhibitor, mTOR complex 2inhibitor, mTOR inhibitor, Mucolipin modulator, Muscarinic receptorantagonist, Myeloperoxidase inhibitor, NACHT LRR PYD domain protein 3inhibitor, NAD synthase modulator, NADPH oxidase inhibitor, Neuropilin 2modulator, Neuroplastin inhibitor, NFE2L2 gene stimulator, NK cellreceptor agonist, NK1 receptor antagonist, NMDA receptor antagonist,NMDA receptor epsilon 2 subunit inhibitor, Non receptor tyrosine kinaseTYK2 antagonist, Non-nucleoside reverse transcriptase inhibitor, Nuclearerythroid 2-related factor 2 stimulator, Nuclear factor kappa Binhibitor, Nuclear factor kappa B modulator, Nuclease stimulator,Nucleolin inhibitor, Nucleoprotein inhibitor, Nucleoprotein modulator,Nucleoside reverse transcriptase inhibitor, Opioid receptor agonist,Opioid receptor antagonist, Opioid receptor mu modulator, Opioidreceptor sigma antagonist 1, Ornithine decarboxylase inhibitor, Outermembrane protein inhibitor, OX40 ligand, p38 MAP kinase alpha inhibitor,p38 MAP kinase inhibitor, p38 MAP kinase modulator, p53 tumor suppressorprotein stimulator, Palmitoyl protein thioesterase 1 inhibitor, Papaininhibitor, PARP inhibitor, PARP modulator, PDE 10 inhibitor, PDE 3inhibitor, PDE 4 inhibitor, PDGF receptor alpha antagonist, PDGFreceptor antagonist, PDGF receptor beta antagonist, Peptidyl-prolylcis-trans isomerase A inhibitor, Peroxiredoxin 6 modulator, PGD2antagonist, PGI2 agonist, P-glycoprotein inhibitor, Phosphoinositide3-kinase inhibitor, Phosphoinositide-3 kinase delta inhibitor,Phosphoinositide-3 kinase gamma inhibitor, Phospholipase A2 inhibitor,Plasma kallikrein inhibitor, Plasminogen activator inhibitor 1inhibitor, Platelet inhibitor, Platelet glycoprotein VI inhibitor,Polo-like kinase 1 inhibitor, Poly ADP ribose polymerase 1 inhibitor,Poly ADP ribose polymerase 2 inhibitor, Polymerase cofactor VP35inhibitor, PPAR alpha agonist, Progesterone receptor agonist, Programmedcell death protein 1 modulator, Prolyl hydroxylase inhibitor,Prostaglandin E synthase-1 inhibitor, Protease inhibitor, Proteasomeinhibitor, Protein arginine deiminase IV inhibitor, Protein tyrosinekinase inhibitor, Protein tyrosine phosphatase beta inhibitor, Proteintyrosine phosphatase-2C inhibitor, Proto-oncogene Mas agonist,Purinoceptor antagonist, Raf protein kinase inhibitor, RANTES ligand,Ras gene inhibitor, Retinoate receptor responder protein 2 stimulator,Rev protein modulator, Ribonuclease stimulator, RIP-1 kinase inhibitor,RNA helicase inhibitor, RNA polymerase inhibitor, RNA polymerasemodulator, S phase kinase associated protein 2 inhibitor, SARScoronavirus 3C protease like inhibitor, Serine protease inhibitor,Serine threonine protein kinase ATR inhibitor, Serine threonine proteinkinase TBK1 inhibitor, Serum amyloid A protein modulator, Signaltransducer CD24 stimulator, Sodium channel stimulator, Sodium glucosetransporter-2 inhibitor, Sphingosine kinase 1 inhibitor, Sphingosinekinase 2 inhibitor, Sphingosine kinase inhibitor,Sphingosine-1-phosphate receptor-1 agonist, Sphingosine-1-phosphatereceptor-1 antagonist, Sphingosine-1-phosphate receptor-1 modulator,Sphingosine-1-phosphate receptor-5 agonist, Sphingosine-I-phosphatereceptor-5 modulator, Spike glycoprotein inhibitor, Src tyrosine kinaseinhibitor, STAT-1 modulator, STAT-3 inhibitor, STAT-5 inhibitor, STAT3gene inhibitor, Stem cell antigen-1 inhibitor, Stimulator of interferongenes protein stimulator, Sulfatase inhibitor, Superoxide dismutasemodulator, Superoxide dismutase stimulator, Syk tyrosine kinaseinhibitor, T cell immunoreceptor Ig ITIM protein inhibitor, T cellreceptor agonist, T cell surface glycoprotein CD28 inhibitor, T-celldifferentiation antigen CD6 inhibitor, T-cell surface glycoprotein CD8stimulator, T-cell transcription factor NFAT modulator, Tankyrase-Iinhibitor, Tankyrase-2 inhibitor, Tek tyrosine kinase receptorstimulator, Telomerase modulator, Tetanus toxin modulator, TGF betareceptor antagonist, TGFB2 gene inhibitor, Thymosin beta 4 ligand,Thyroid hormone receptor beta agonist, Tissue factor inhibitor, Tissueplasminogen activator modulator, Tissue plasminogen activatorstimulator, TLR agonist, TLR modulator, TLR-2 agonist, TLR-2 antagonist,TLR-3 agonist, TLR-4 agonist, TLR-4 antagonist, TLR-6 agonist, TLR-7agonist, TLR-7 antagonist, TLR-8 antagonist, TLR-9 agonist, TMPRSS2 geneinhibitor, TNF alpha ligand inhibitor, TNF alpha ligand modulator, TNFbinding agent, TNF gene inhibitor, Topoisomerase inhibitor,Transcription factor EB stimulator, Transferrin modulator, Transketolaseinhibitor, Translocation associated protein inhibitor, Transmembraneserine protease 2 inhibitor, Transthyretin modulator, TREM receptor 1antagonist, TRP cation channel C1 modulator, TRP cation channel C6inhibitor, TRP cation channel V6 inhibitor, Trypsin 1 inhibitor, Trypsin2 inhibitor, Trypsin 3 inhibitor, Trypsin inhibitor, Tubulin alphainhibitor, Tubulin beta inhibitor, Tumor necrosis factor 14 ligandinhibitor, TYK2 gene inhibitor, Type I IL-1 receptor antagonist,Tyrosine protein kinase ABL1 inhibitor, Ubiquinol cytochrome C reductase14 kDa inhibitor, Ubiquitin ligase modulator, Unspecified GPCR agonist,Unspecified cytokine receptor modulator, Unspecified enzyme stimulator,Unspecified gene inhibitor, Unspecified receptor modulator, Urokinaseplasminogen activator inhibitor, Vascular cell adhesion protein 1agonist, Vasodilator, VEGF ligand inhibitor, VEGF receptor antagonist,VEGF-1 receptor antagonist, VEGF-1 receptor modulator, VEGF-2 receptorantagonist, VEGF-3 receptor antagonist, Vimentin inhibitor, Vimentinmodulator, VIP receptor agonist, Viral envelope protein inhibitor, Viralprotease inhibitor, Viral protease modulator, Viral protein targetmodulator, Viral ribonuclease inhibitor, Viral structural proteinmodulator, Vitamin D3 receptor agonist, X-linked inhibitor of apoptosisprotein inhibitor, Xanthine oxidase inhibitor, or Zonulin inhibitor.

In some embodiments, the compounds and compositions of the presentdisclosure may be administered in combination with a Sars-Cov-2treatment, such as parenteral fluids (including dextrose saline andRinger's lactate), nutrition, antibiotics (including azithromycin,metronidazole, amphotericin B, amoxicillin/clavulanate,trimethoprim/sulfamethoxazole, R-327 and cephalosporin antibiotics, suchas ceftriaxone and cefuroxime), antifungal prophylaxis, fever and painmedication, antiemetic (such as metoclopramide) and/or antidiarrhealagents, vitamin and mineral supplements (including Vitamin K, vitamin D,cholecalciferol, vitamin C and zinc sulfate), anti-inflammatory agents(such as ibuprofen or steroids), corticosteroids such as dexamethasone,methylprednisolone, prednisone, mometasone, immunomodulatory medications(eg interferon), vaccines, and pain medications.

In some embodiments, the additional therapeutic agent is an Abl tyrosinekinase inhibitor, such as radotinib or imatinib.

In some embodiments, the additional therapeutic agent is an acetaldehydedehydrogenase inhibitor, such as ADX-629.

In some embodiments, the additional therapeutic agent is an adenosine A3receptor agonist, such as piclidenoson.

In some embodiments, the additional therapeutic agent is anadrenomedullin ligand such as adrenomedullin.

In some embodiments, the additional therapeutic agent is a p38 MAPK+PPARgamma agonist/insulin sensitizer such as KIN-001.

In some embodiments, the additional therapeutic agent is a PPAR alphaagonist such as DWTC-5101 (fenofibrate choline).

In some embodiments, the additional therapeutic agent is a cyclophilininhibitor such as rencofilstat.

In some embodiments, the additional therapeutic is a p38 MAP kinaseinhibitor such as PRX-201 or Gen-1124.

In some embodiments, the additional therapeutic agent is an aldosereductase inhibitor, such as caficrestat.

In some embodiments, the additional therapeutic agent is an AMPAreceptor modulator, such as traneurocin.

In some embodiments, the additional therapeutic agent is an annexin A5stimulator, such as AP-01 or SY-005.

In some embodiments, the additional therapeutic agent is an apelinreceptor agonist, such as CB-5064MM.

In some embodiments, the additional therapeutic agent is ananti-coagulant, such as heparins (heparin and low molecular weightheparin), aspirin, apixaban, dabigatran, edoxaban, argatroban,enoxaparin, or fondaparinux.

In some embodiments, the additional therapeutic agent is an androgenreceptor antagonist such as bicalutamide, enzalutamide, or pruxelutamide(proxalutamide).

In some embodiments, the additional therapeutic agent is anti-hypoxic,such as trans-sodium crocetinate.

In some embodiments, the additional therapeutic agent is ananti-thrombotic, such as defibrotide, rivaroxaban, alteplase, tirofiban,clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, ortenecteplase.

In some embodiments, the additional therapeutic agent is anantihistamine, such as cloroperastine or clemastine.

In some embodiments, the additional therapeutic agent is anapolipoprotein A1 agonist, such as CER-001.

In some embodiments, the additional therapeutic agent is a phospholipaseA2 inhibitor, such as icosapent ethyl.

In some embodiments, the additional therapeutic agent is an axl tyrosinekinase receptor inhibitor, such as bemcentinib.

In some embodiments, the additional therapeutic agent is acorticosteroid/beta 2 adrenoceptor agonist, such asbudesonide+formoterol fumarate.

In some embodiments, the additional therapeutic agent is a BETbromodomain inhibitor/APOA1 gene stimulator such as apabetalone.

In some embodiments, the additional therapeutic agent is a bloodclotting modulator, such as lanadelumab.

In some embodiments, the additional therapeutic agent is a bradykinin B2receptor antagonist, such as icatibant.

In some embodiments, the additional therapeutic agent is an EGFR geneinhibitor/Btk tyrosine kinase inhibitor, such as abivertinib.

In some embodiments, the additional therapeutic agent is a Btk tyrosinekinase inhibitor, such as ibrutinib or zanubrutinib.

In some embodiments, the additional therapeutic agent is acalpain-III/IX inhibitor, such as BLD-2660.

In some embodiments, the additional therapeutic agent is a cannabinoidCB2 receptor agonist, such as onternabez or PPP-003.

In some embodiments, the additional therapeutic agent is a Ca2+ releaseactivated Ca2+ channel 1 inhibitor, such as zegocractin (CM-4620).

In some embodiments, the additional therapeutic agent is an ATRinhibitor, such as berzosertib.

In some embodiments, the additional therapeutic agent is a cadherin-5modulator, such as FX-06.

In some embodiments, the additional therapeutic agent is a casein kinaseII inhibitor, such as silmitasertib.

In some embodiments, the additional therapeutic agent is a caspaseinhibitor, such as emricasan.

In some embodiments, the additional therapeutic agent is a catalasestimulator/superoxide dismutase stimulator, such as MP-1032.

In some embodiments, the additional therapeutic agent is a CCR2chemokine antagonist/CCR5 chemokine antagonist such as cenicriviroc.

In some embodiments, the additional therapeutic agent is a CCR5chemokine antagonist, such as maraviroc or leronlimab.

In some embodiments, the additional therapeutic agent is a CD122agonist/IL-2 receptor agonist, such as bempegaldesleukin.

In some embodiments, the additional therapeutic agent is a CD73agonist/interferon beta ligand, such as FP-1201.

In some embodiments, the additional therapeutic agent is a cholesterolester transfer protein inhibitor, such as dalcetrapib.

In some embodiments, the additional therapeutic agent is aMannan-binding lectin serine protease/complement C1s subcomponentinhibitor/myeloperoxidase inhibitor, such as RLS-0071.

In some embodiments, the additional therapeutic agent is a complement C5factor inhibitor/leukotriene BLT receptor antagonist, such as nomacopan.

In some embodiments, the additional therapeutic agent is a complement C5factor inhibitor, such as eculizumab, STSA-1002, zilucoplan.

In some embodiments, the additional therapeutic agent is a CXCR4chemokine antagonist, such as plerixafor or motixafortide.

In some embodiments, the additional therapeutic agent is a cytochromeP450 3A4 inhibitor/peptidyl-prolyl cis-trans isomerase A inhibitor, suchas alisporivir.

In some embodiments, the additional therapeutic agent is a cysteineprotease inhibitor, such as SLV-213.

In some embodiments, the additional therapeutic agent is adihydroorotate dehydrogenase inhibitor, such as Meds-433, brequinar,RP-7214, or emvododstat.

In some embodiments, the additional therapeutic agent is adehydropeptidase-1 modulator, such as Metablok.

In some embodiments, the additional therapeutic agent is adihydroorotate dehydrogenase inhibitor/IL-17 antagonist, such asvidofludimus.

In some embodiments, the additional therapeutic agent is a diuretic,such as an aldosterone antagonist, such as spironolactone.

In some embodiments, the additional therapeutic agent is adeoxyribonuclease I stimulator, such as GNR-039 or dornase alfa.

In some embodiments, the additional therapeutic agent is a NETinhibitor, such as NTR-441.

In some embodiments, the additional therapeutic agent is adihydroceramide delta 4 desaturase inhibitor/sphingosine kinase 2inhibitor, such as opaganib.

In some embodiments, the additional therapeutic agent is a DNAmethyltransferase inhibitor, such as azacytidine.

In some embodiments, the additional therapeutic agent is an LXRantagonist, such as larsucosterol.

In some embodiments, the additional therapeutic agent is a dipeptidylpeptidase I inhibitor, such as brensocatib.

In some embodiments, the additional therapeutic agent is a proteinarginine deiminase IV inhibitor, such as JBI-1044.

In some embodiments, the additional therapeutic agent is an elongationfactor 1 alpha 2 modulator, such as plitidepsin.

In some embodiments, the additional therapeutic agent is a eukaryoticinitiation factor 4A-I inhibitor, such as zotatifin.

In some embodiments, the additional therapeutic agent is an exo-alphasialidase modulator, such as DAS-181.

In some embodiments, the additional therapeutic agent is an exportin 1inhibitor, such as selinexor.

In some embodiments, the additional therapeutic agent is a fractalkineligand inhibitor, such as KAND-567.

In some embodiments, the additional therapeutic agent is a FYVE fingerphosphoinositide kinase inhibitor/IL-12 receptor antagonist/IL-23antagonist, such as apilimod dimesylate.

In some embodiments, the additional therapeutic agent is a GABA Areceptor modulator, such as brexanolone.

In some embodiments, the additional therapeutic agent is aglucocorticoid receptor agonist, such as ciclesonide, hydrocortisone,dexamethasone, dexamethasone phosphate, or 101-PGC-005.

In some embodiments, the additional therapeutic agent is a GM-CSFreceptor agonist, such as sargramostim.

In some embodiments, the additional therapeutic agent is a GPCR agonist,such as esuberaprost sodium.

In some embodiments, the additional therapeutic agent is a Griffithsinmodulator, such as Q-Griffithsin.

In some embodiments, the additional therapeutic agent is a leukotrieneD4 antagonist, such as montelukast.

In some embodiments, the additional therapeutic agent is a histamine H1receptor antagonist, such as ebastine, tranilast, levocetirizinedihydrochloride.

In some embodiments, the additional therapeutic agent is a histamine H2receptor antagonist, such as famotidine.

In some embodiments, the additional therapeutic agent is a heat shockprotein stimulator/insulin sensitizer/PARP inhibitor, such as BGP-15.

In some embodiments, the additional therapeutic agent is a histoneinhibitor, such as STC-3141.

In some embodiments, the additional therapeutic agent is a histonedeacetylase-6 inhibitor, such as CKD-506.

In some embodiments, the additional therapeutic agent is a HIF prolylhydroxylase-2 inhibitor, such as desidustat.

In some embodiments, the additional therapeutic agent is an HIF prolylhydroxylase inhibitor, such as vadadustat.

In some embodiments, the additional therapeutic agent is an IL-8receptor antagonist, such as reparixin.

In some embodiments, the additional therapeutic agent is an IL-7receptor agonist, such as CYT-107.

In some embodiments, the additional therapeutic agent is an IL-7receptor agonist/interleukin-7 ligand, such as efineptakin alfa.

In some embodiments, the additional therapeutic agent is an IL-22agonist, such as efmarodocokin alfa.

In some embodiments, the additional therapeutic agent is an IL-22agonist/interleukin 22 ligand, such as F-652.

In some embodiments, the additional therapeutic agent is targeted toIL-33, such as tozorakimab.

In some embodiments, the additional therapeutic is an IL-15 agonist suchas nogapendekin alfa.

In some embodiments, the additional therapeutic agent is an integrinalpha-V/beta-1 antagonist/integrin alpha-V/beta-6 antagonist, such asbexotegrast.

In some embodiments, the additional therapeutic agent is an interferonalpha 2 ligand, such as interferon alfa-2b or Virafin.

In some embodiments, the additional therapeutic agent is an interferonbeta ligand, such as interferon beta-1a follow-on biologic, interferonbeta-1b, or SNG-001.

In some embodiments, the additional therapeutic agent is an interferonreceptor modulator, such as peginterferon lambda-1a.

In some embodiments, the additional therapeutic agent is aninterleukin-2 ligand, such as aldesleukin.

In some embodiments, the additional therapeutic agent is an IRAK-4protein kinase inhibitor, such as zimlovisertib.

In some embodiments, the additional therapeutic agent is a JAKinhibitor, for example the additional therapeutic agent is baricitinib,filgotinib, jaktinib, tofacitinib, or nezulcitinib (TD-0903).

In some embodiments, the additional therapeutic agent is a neutrophilelastase inhibitor, such as alvelestat.

In some embodiments, the additional therapeutic agent is a lungsurfactant associated protein D modulator, such as AT-100.

In some embodiments, the additional therapeutic agent is a plasmakallikrein inhibitor, such as donidalorsen.

In some embodiments, the additional therapeutic agent is a lysinespecific histone demethylase 1/MAO B inhibitor, such as vafidemstat.

In some embodiments, the additional therapeutic agent is aMannan-binding lectin serine protease inhibitor, such as conestat alfa.

In some embodiments, the additional therapeutic agent is a maxi Kpotassium channel inhibitor, such as ENA-001.

In some embodiments, the additional therapeutic agent is a MEK proteinkinase inhibitor, such as zapnometinib.

In some embodiments, the additional therapeutic agent is a MEK-1 proteinkinase inhibitor/Ras gene inhibitor, such as antroquinonol.

In some embodiments, the additional therapeutic agent is a melanocortinMC1 receptor agonist, such as PL-8177.

In some embodiments, the additional therapeutic agent is a melanocortinMC1/MC3 receptor agonist, such as resomelagon acetate.

In some embodiments, the additional therapeutic agent is a matrixmetalloprotease-12 inhibitor, such as FP-025.

In some embodiments, the additional therapeutic agent is a NACHT LRR PYDdomain protein 3 inhibitor, such as dapansutrile, DFV-890, or ZYIL-1.

In some embodiments, the additional therapeutic agent is a NADPH oxidaseinhibitor, such as isuzinaxib.

In some embodiments, the additional therapeutic agent is a neuropilin 2modulator, such as efzofitimod.

In some embodiments, the additional therapeutic agent is an NK1 receptorantagonist, such as aprepitant or tradipitant.

In some embodiments, the additional therapeutic agent is an NMDAreceptor antagonist, such as transcrocetin or ifenprodil.

In some embodiments, the additional therapeutic agent is a nuclearfactor kappa B inhibitor/p38 MAP kinase inhibitor, such as zenuzolac.

In some embodiments, the additional therapeutic agent is an ornithinedecarboxylase inhibitor, such as eflornithine.

In some embodiments, the additional therapeutic agent is an opioidreceptor sigma antagonist 1, such as MR-309.

In some embodiments, the additional therapeutic agent is a PGD2antagonist, such as asapiprant.

In some embodiments, the additional therapeutic agent is a PDGF receptorantagonist/TGF beta receptor antagonist/p38 MAP kinase inhibitor, suchas deupirfenidone.

In some embodiments, the additional therapeutic agent is a phospholipaseA2 inhibitor, such as varespladib methyl.

In some embodiments, the additional therapeutic agent is aphosphoinositide 3-kinase inhibitor/mTOR complex inhibitor, such asdactolisib.

In some embodiments, the additional therapeutic agent is a mTORinhibitor, such as sirolimus.

In some embodiments, the additional therapeutic agent is aphosphoinositide-3 kinase delta/gamma inhibitor, such as duvelisib.

In some embodiments, the additional therapeutic agent is a plasminogenactivator inhibitor 1 inhibitor, such as TM-5614.

In some embodiments, the additional therapeutic agent is a proteintyrosine phosphatase beta inhibitor, such as razuprotafib.

In some embodiments, the additional therapeutic agent is a RIP-1 kinaseinhibitor, such as DNL-758 or SIR-0365.

In some embodiments, the additional therapeutic agent is a Rev proteinmodulator, such as obefazimod.

In some embodiments, the additional therapeutic agent is an S phasekinase associated protein 2 inhibitor, such as niclosamide, SCAI-502 orDWRX-2003.

In some embodiments, the additional therapeutic agent is a signaltransducer CD24 stimulator, such as EXO-CD24.

In some embodiments, the additional therapeutic agent is a sodiumglucose transporter-2 inhibitor, such as dapagliflozin propanediol.

In some embodiments, the additional therapeutic agent is a sodiumchannel stimulator, such as solnatide.

In some embodiments, the additional therapeutic agent is asphingosine-1-phosphate receptor-1 agonist/sphingosine-1-phosphatereceptor-5 agonist, such as ozanimod.

In some embodiments, the additional therapeutic agent is a non-steroidalanti-inflammatory drug, such as Ampion.

In some embodiments, the additional therapeutic agent is a superoxidedismutase stimulator, such as avasopasem manganese.

In some embodiments, the additional therapeutic agent is a Syk tyrosinekinase inhibitor, such as fostamatinib disodium.

In some embodiments, the additional therapeutic agent is a Tie2 tyrosinekinase receptor agonist, such as AV-001.

In some embodiments, the additional therapeutic agent is a TGFB2 geneinhibitor, such as trabedersen.

In some embodiments, the additional therapeutic agent is a tissue factorinhibitor, such as AB-201.

In some embodiments, the additional therapeutic agent is a TLR-3agonist, such as rintatolimod.

In some embodiments, the additional therapeutic agent is a TLR-4antagonist, such as ApTLR-4FT, EB-05, or eritoran.

In some embodiments, the additional therapeutic agent is a TLR-7/8antagonist, such as enpatoran.

In some embodiments, the additional therapeutic agent is a TLR-2/6agonist, such as INNA-051.

In some embodiments, the additional therapeutic agent is a TLR-7agonist, such as PRTX-007 or APR-002.

In some embodiments, the additional therapeutic agent is a TLR agonist,such as PUL-042.

In some embodiments, the additional therapeutic agent is a TLR-4agonist, such as REVTx-99.

In some embodiments, the additional therapeutic agent is a TLR-2/4antagonist, such as VB-201.

In some embodiments, the additional therapeutic agent is a TNF alphaligand inhibitor, such as pegipanermin.

In some embodiments, the additional therapeutic agent is a type I IL-1receptor antagonist, such as anakinra.

In some embodiments, the additional therapeutic agent is a TREM receptor1 antagonist, such as nangibotide.

In some embodiments, the additional therapeutic agent is a trypsininhibitor, such as ulinastatin.

In some embodiments, the additional therapeutic agent is a tubulininhibitor such as sabizabulin, CCI-001, PCNT-13, CR-42-24, albendazole,entasobulin, SAR-132885, or ON-24160.

In some embodiments, the additional therapeutic agent is a VIP receptoragonist, such as aviptadil.

In some embodiments, the additional therapeutic agent is a xanthineoxidase inhibitor, such as oxypurinol.

In some embodiments, the additional therapeutic agent is a vasodilator,such as iloprost, epoprostenol (VentaProst), zavegepant, TXA-127,USB-002, ambrisentan, nitric oxide nasal spray (NORS), pentoxifylline,propranolol, RESP301, sodium nitrite, or dipyridamole.

In some embodiments, the additional therapeutic agent is a vitamin D3receptor agonist, such as cholecalciferol.

In some embodiments, the additional therapeutic agent is a zonulininhibitor, such as larazotide acetate.

In some embodiments, the additional therapeutic agent is a syntheticretinoid derivative, such as fenretinide.

In some embodiments, the additional therapeutic agent is a glucosemetabolism inhibitor such as WP-1122 or WP-1096.

In some embodiments, the additional therapeutic agent is adalimumab,AT-H201, 2-deoxy-D-glucose, AD-17002, AIC-649, AMTX-100, astodrimer,AZD-1656, belapectin, bitespiramycin, bucillamine, budesonide,CNM-AgZn-17, Codivir, CT-38, danicopan, didodecyl methotrexate, DW-2008S(DW-2008), EDP-1815, EG-009A, Fabencov, Gamunex, genistein, GLS-1200,hzVSF-v13, imidazolyl ethanamide pentandioic acid, IMM-101, MAS-825,MRG-001, Nasitrol, Nylexa, olverembatinib, OP-101, OPN-019, Orynotiderhesus theta defensin-1, pyronaridine+artesunate, dapsone, RPH-104,sodium pyruvate, Sulforadex, tafenoquine, TB-006, telacebec, Tempol,TL-895, thimesoral, trimodulin, XC-221, XC-7, zunsemetinib, metforminglycinate, lucinactant, EOM-613, mosedipimod, ivermectin, leflunomide,ibudilast, RBT-9, raloxifene, prothione, gemcabene, or idronoxil.

In some embodiments, the additional therapeutic agent is a CD73antagonist, such as AK-119.

In some embodiments, the additional therapeutic agent is a CD95 proteinfusion, such as asunercept.

In some embodiments, the additional therapeutic agent is a complementfactor C2 modulator, such as ARGX-117.

In some embodiments, the additional therapeutic agent is a complement C3inhibitor, such as AMY-101 or NGM-621.

In some embodiments, the additional therapeutic agent is a CXC10chemokine ligand inhibitor, such as EB-06.

In some embodiments, the additional therapeutic agent is a cytotoxicT-lymphocyte protein-4 fusion protein, such as abatacept.

In some embodiments, the additional therapeutic agent is an anti-S.aureus antibody, such as tosatoxumab.

In some embodiments, the additional therapeutic agent is an anti-LPSantibody, such as IMM-124-E.

In some embodiments, the additional therapeutic agent is anadrenomedullin ligand inhibitor, such as enibarcimab.

In some embodiments, the additional therapeutic agent is a basigininhibitor, such as meplazumab.

In some embodiments, the additional therapeutic agent is a CD3antagonist, such as foralumab.

In some embodiments, the additional therapeutic agent is a connectivetissue growth factor ligand inhibitor, such as PRS-220, pamrevlumab.

In some embodiments, the additional therapeutic agent is a complementC5a factor inhibitor, such as BDB-1 or vilobelimab.

In some embodiments, the additional therapeutic agent is a complement C5factor inhibitor, such as ravulizumab.

In some embodiments, the additional therapeutic agent is amannan-binding lectin serine protease-2 inhibitor, such as narsoplimab.

In some embodiments, the additional therapeutic agent is a GM-CSFmodulator, such as STSA-1005, gimsilumab, namilumab, plonmarlimab,otilimab, or lenzilumab.

In some embodiments, the additional therapeutic agent is a heat shockprotein inhibitor/IL-6 receptor antagonist, such as siltuximab.

In some embodiments, the additional therapeutic agent is an IL-6receptor antagonist, such as clazakizumab, levilimab, olokizumab,tocilizumab, or sirukumab.

In some embodiments, the additional therapeutic agent is an IL-8receptor antagonist, such as BMS-986253.

In some embodiments, the additional therapeutic agent is aninterleukin-1 beta ligand inhibitor, such as canakinumab.

In some embodiments, the additional therapeutic agent is an interferongamma ligand inhibitor, such as emapalumab.

In some embodiments, the additional therapeutic agent is an anti-ILT7antibody, such as daxdilimab.

In some embodiments, the additional therapeutic agent is a monocytedifferentiation antigen CD14 inhibitor, such as atibuclimab.

In some embodiments, the additional therapeutic agent is a plasmakallikrein inhibitor, such as lanadelumab.

In some embodiments, the additional therapeutic agent is a plateletglycoprotein VI inhibitor, such as glenzocimab.

In some embodiments, the additional therapeutic agent is a T-celldifferentiation antigen CD6 inhibitor, such as itolizumab.

In some embodiments, the additional therapeutic agent is a TNF alphaligand inhibitor/TNF binding agent, such as infliximab.

In some embodiments, the additional therapeutic agent is an anti-LIGHTantibody, such as AVTX-002.

In some embodiments, the additional therapeutic agent is IMC-2(valacyclovir+celecoxib), or AXA-1125.

In some embodiments, the additional therapeutic agent is COVID-HIG.

In some embodiments, a compound of the disclosure, or a pharmaceuticallyacceptable salt thereof, is co-administered with one or more agentsuseful for the treatment and/or prophylaxis of COVID-19.

Non-limiting examples of such agents include corticosteroids, such asdexamethasone, hydrocortisone, methylprednisolone, or prednisone;interleukin-6 (IL-6) receptor blockers, such as tocilizumab orsarilumab; Janus kinase (JAK) inhibitors, such as baricitinib,ruxolitinib, or tofacitinib; and antiviral agents, such as molnupiravir,sotrovimab, or remdesivir.

In further embodiments, a compound of the disclosure, or apharmaceutically acceptable salt thereof, is co-administered with two ormore agents useful for the treatment of COVID-19.

Agents useful for the treatment and/or prophylaxis of COVID-19 includebut are not limited to a compound of the disclosure and two additionaltherapeutic agents, such as nirmatrelvir and ritonavir, casirivimab andimdevimab, or ruxolitinib and tofacitinib.

In some embodiments, the additional therapeutic agent is an antiviralagent. In some embodiments, the antiviral agent is an entry inhibitor.In some embodiments, the antiviral agent is a protease inhibitor. Insome embodiments, the antiviral agent is an RNA polymerase inhibitor.

In some embodiments, the additional therapeutic agent is anRNA-dependent RNA polymerase (RdRp) inhibitor.

In some embodiments, the antiviral agent is selected from angiotensinconverting enzyme 2 inhibitors, angiotensin converting enzyme 2modulators, angiotensin converting enzyme 2 stimulators, angiotensin IIAT-2 receptor agonists, angiotensin II AT-2 receptor antagonists,angiotensin II receptor modulators, coronavirus nucleoproteinmodulators, coronavirus small envelope protein modulators, coronavirusspike glycoprotein inhibitors, coronavirus spike glycoproteinmodulators, SARS-CoV-2 envelope small membrane protein inhibitors,SARS-CoV-2 envelope small membrane protein modulators, SARS-CoV-2 MProinhibitors, SARS-CoV-2 non structural protein 8 modulators, SARS-CoV-2nucleoprotein inhibitors, SARS-CoV-2 nucleoprotein modulators,SARS-CoV-2 protein 3a inhibitors, SARS-CoV-2 replicase polyprotein 1ainhibitors, SARS-CoV-2 replicase polyprotein 1a modulators, SARS-CoV-2replicase polyprotein lab inhibitors, SARS-CoV-2 replicase polyproteinlab modulators, SARS-CoV-2 spike glycoprotein inhibitors, SARS-CoV-2spike glycoprotein modulators, SARS-CoV-2 structural glycoproteinmodulators, papain inhibitors, protease inhibitors, protease modulators,RNA polymerase inhibitors, RNA polymerase modulators, RNA-dependent RNApolymerase (RdRp) inhibitors, SARS coronavirus 3C protease likeinhibitors, SARS-CoV-2 nsp14 methyltransferase enzyme inhibitor,3CLpro/Mpro inhibitors, serine protease inhibitors, transmembrane serineprotease 2 inhibitors, transmembrane serine protease 2 modulators, viralenvelope protein inhibitors, viral protease inhibitors, viral proteasemodulators, viral protein target modulators, viral ribonucleaseinhibitors, and viral structural protein modulators.

In some embodiments, the additional therapeutic agent is an entryinhibitor. For example, in some embodiments the additional therapeuticagent is an ACE2 inhibitor, a fusion inhibitor, or a protease inhibitor.

In some embodiments, the additional therapeutic agent is an angiotensinconverting enzyme 2 inhibitor, such as SBK-001.

In some embodiments, the additional therapeutic agent is an angiotensinconverting enzyme 2 modulator, such as neumifil or JN-2019.

In some embodiments, the additional therapeutic agent is an entryinhibitor such as MU-UNMC-1.

In some embodiments, the additional therapeutic agent is an angiotensinconverting enzyme 2 stimulator, such as alunacedase alfa.

In some embodiments, the additional therapeutic agent is an angiotensinII AT-2 receptor agonist, such as VP-01.

In some embodiments, the additional therapeutic agent is an ACE IIreceptor antagonist, such as DX-600.

In some embodiments, the additional therapeutic agent is an angiotensinII receptor modulator, such as TXA-127.

In some embodiments, the additional therapeutic agent is a transmembraneserine protease 2 modulator, such as BC-201.

In some embodiments, the additional therapeutic agent is a viralenvelope protein inhibitor, such as MXB-9 or MXB-004.

In some embodiments, the additional therapeutic agent is a RNAi agentsuch as ARO-COV or SNS-812.

In some embodiments, the additional therapeutic agent is a vaccine. Forexample, in some embodiments, the additional therapeutic agent is a DNAvaccine, RNA vaccine, live-attenuated vaccine, inactivated vaccine(i.e., inactivated SARS-CoV-2 vaccine), therapeutic vaccine,prophylactic vaccine, protein-based vaccine, viral vector vaccine,cellular vaccine, or dendritic cell vaccine.

In some embodiments, the additional therapeutic agent is a vaccine suchas tozinameran, NVX-CoV2373, elasomeran, KD-414, Ad26.COV2-S, Vaxzevria,SCB-2019, AKS-452, VLA-2001, HDT-301, S-268019, MVC-COV1901,mRNA-1273.214, mRNA-1273.213, mRNA-1273.222, NVX-CoV2515, Covaxin,BBIBP-CorV, GBP-510, mRNA-1273.351+mRNA-1273.617 (SARS-CoV-2 multivalentmRNA vaccine, COVID-19), Ad5-nCoV, Omicron-based COVID-19 vaccine (mRNAvaccine, COVID-19), mRNA-1073, mRNA-1273.214, mRNA-1230, mRNA-1283,Omicron-based COVID-19 vaccine, SARS-CoV-2 Protein Subunit RecombinantVaccine, Sputnik M, ZyCoV-D, COVID-19 XWG-03, mRNA-1273.529, mRNA-1010,CoronaVac, AZD-2816, Sputnik V, inactivated SARS-CoV-2 vaccine (Verocell, COVID-19), DS-5670, PHH-1V, INO-4800, UB-612, coronavirus vaccine(whole-virion, inactivated/purified), ReCOV, MT-2766, ARCT-154, SP-0253,CORBEVAX, mRNA-1273.211, ZF-2001, Sputnik Light, recombinant proteinvaccine (COVID-19/SARS-CoV-2 infection), VSV vector-based vaccinetargeting spike glycoprotein (COVID-19), VLA-2101, GRT-R912, GRAd-COV2,VPM-1002, COViran Barekat, Ad5-nCoV-IH, ARCoV, Covax-19, recombinantSARS-CoV-2 vaccine (protein subunit/CHO cell, COVID-19), BBV-154, RAZICov Pars, COVID-19 vaccine (inactivated/Vero cells/intramuscular,SARS-CoV-2 infection), COVID-19 vaccine (inactivated, Verocells/intramuscular), BNT-162b2s01, BNT-162b4, BNT-162b5, BNT-162b2 Omi,BNT-162b2 bivalent, CIGB-66, mRNA-1273.617, Mycobacterium w, ERUCOV-VAC,AG-0301-COVID19, fakhravac, AV-COVID-19, peptide vaccine (COVID-19),Nanocovax, SARS-CoV-2 vaccine (inactivated/Vero cells/intramuscular,COVID-19), QAZCOVID-IN, S-875670 nasal vaccine, VTP-500, or BNT162b5.

In some embodiments, the additional therapeutic agent is a proteaseinhibitor. For example, in some embodiments the additional therapeuticagent is a 3C-like cysteine protease inhibitor (3CLpro, also called Mainprotease, Mpro), a papain-like protease inhibitor (PLpro), serineprotease inhibitor, or transmembrane serine protease 2 inhibitor(TMPRSS2).

In some embodiments, the additional therapeutic agent is a 3CLpro/Mproinhibitor, such as CDI-873, GC-373, GC-376, PBI-0451, UCI-1, bofutrelvir(FB-2001, DC-402234), DC-402267, GDI-4405, RAY-1216, MPI-8, SH-879,SH-580, EDP-235, VV-993, CDI-988, MI-30, nirmatrelvir, ensitrelvir,ASC-11, EDDC-2214, SIM-0417, CDI-45205, COR-803, ALG-097111, TJC-642,CVD-0013943, eravacycline, cynarine, or prexasertib.

In some embodiments, the additional therapeutic agent is a papain-likeprotease inhibitor (PLpro), such as SBFM-PL4 or GRL-0617.

In some embodiments, the additional therapeutic agent is a SARS-CoV-2helicase Nsp13 inhibitor, such as EIS-4363.

In some embodiments, the additional therapeutic agent is a SARS-CoV-2helicase Nsp14 inhibitor, such as TO-507.

In some embodiments, the additional therapeutic agent is a SARS-CoV-2spike (S) and protease modulator, such as ENU-200.

In some embodiments, the additional therapeutic agent is a proteaseinhibitor, such as ALG-097558 or MRX-18.

In some embodiments, the additional therapeutic agent is a serineprotease inhibitor, such as upamostat, nafamostat, camostat mesylate,nafamostat mesylate, or camostat.

In some embodiments, the additional therapeutic agent is a3CLpro/transmembrane serine protease 2 inhibitor, such as SNB-01(pentarlandir) or SNB-02.

In some embodiments, the additional therapeutic agent is a viralprotease inhibitor, such as Pan-Corona, Cov-X, or bepridil.

In some embodiments, the additional therapeutic agent is an RNApolymerase inhibitor.

For example, in some embodiments, the additional therapeutic agent is anRNA polymerase inhibitor, or an RNA-dependent RNA polymerase (RdRp)inhibitor.

In some embodiments, the additional therapeutic agent is anRNA-dependent RNA polymerase (RdRp) inhibitor, such as remdesivir,NV-CoV-2-R, NV-CoV-1 encapsulated remdesivir, GS-621763, GS-5245,GS-441524, DEP remdesivir, ATV-006, VV-116, LGN-20, CMX-521 andcompounds disclosed in WO2022142477, WO2021213288, WO2022047065.

In some embodiments, the additional therapeutic agent is an RNApolymerase inhibitor, such as molnupiravir (EIDD-2801), favipiravir,bemnifosbuvir, sofosbuvir, ASC-10, or galidesivir.

In some embodiments, the additional therapeutic agent is viral entryinhibitor, such as brilacidin.

In some embodiments, the additional therapeutic agent is an antibodythat binds to a coronavirus, for example an antibody that binds to SARSor MERS.

In some embodiments, the additional therapeutic agent is an antibody,for example a monoclonal antibody. For example, the additionaltherapeutic agent is an antibody against SARS-CoV-2, neutralizingnanobodies, antibodies that target the SARS-CoV-2 spike protein, fusionproteins, multispecific antibodies, and antibodies that can neutralizeSARS-CoV-2 (SARS-CoV-2 neutralizing antibodies).

In some embodiments, the additional therapeutic agent is an antibodythat targets specific sites on ACE2. In some embodiments, the additionaltherapeutic agent is a polypeptide targeting SARS-CoV-2 spike protein(S-protein).

In some embodiments, the additional therapeutic agent is a SARS-CoV-2virus antibody.

In some embodiments, the antibody is ABBV-47D11, COVI-GUARD (STI-1499),C144-LS+C135-LS, DXP-604, JMB-2002, LY-CovMab, bamlanivimab (LY-CoV555),GIGA-2050, IBI-314, S309, SAB-185, etesevimab (CB6), COR-101, JS016,VNAR, VIR-7832 and/or sotrovimab (VIR-7831), casirivimab+imdevimab(REGN-COV2 or REGN10933+RGN10987), BAT2020, BAT2019, 47D11, YBSW-015, orPA-001.

In some embodiments, the additional therapeutic agent is STI-9199(COVI-SHIELD), STI-9167 or AR-701 (AR-703 and AR-720).

In some embodiments, the additional therapeutic agent is BRII-196,BRII-198, ADG-10, adintrevimab (ADG-20), ABP-300, BA-7208, BI-767551,BHV-1200, CT-P63, JS-026, sotrovimab (GSK-4182136),tixagevimab+cilgavimab (AZD-7442), regdanvimab, SAB-301, AOD-01,plutavimab (COVI-AMG), 9MW-3311 (MW-33), DXP-593, BSVEQAb,anti-SARS-CoV-2 IgY, COVID-EIG, CSL-760, F-61, REGN-3048-3051,SARS-CoV-2 monoclonal antibodies (COVID-19, ADM-03820), enuzovimab(H1FB-30132A), INM-005, SCTA01, TY-027, XAV-19,amubarvimab+romlusevimab, SCTA-01, bebtelovimab, beludavimab, IBI-0123,IGM-6268. FYB-207, FS-2101, RBT-0813, REGN-14256, REGN-14284, SPKM-001,XVR-011, TB202-3, TB181-36, TB339-031, LMN-301, LQ-050, COVAB-36,MAD-0004J08, STI-2099, TATX-03, TZLS-501, ZCB-11 or ACV-200-17.

In some embodiments, the additional therapeutic agent is an engineeredACE-2-IgG1-Fc-fusion protein targeting SARS-Cov-2 RBD, such as EU-129,bivalent ACE2-IgG Fc null fusion protein (SI-F019).

In some embodiments, the additional therapeutic agent is an ACE2-Fcreceptor fusion protein, such as HLX-71.

In some embodiments, the additional therapeutic agent is ensovibep.

In some embodiments, the additional therapeutic agent is SYZJ-001.

In some embodiments, the additional therapeutic agent is an HIV-1protease inhibitor, such as ASC-09F (ASC-09+ritonavir) orlopinavir+ritonavir.

In some embodiments, the additional therapeutic agent is anon-nucleoside reverse transcriptase inhibitor, such as elsulfavirine.

In some embodiments, the additional therapeutic agent is a nucleosidereverse transcriptase inhibitor, such as azvudine.

In some embodiments, the additional therapeutic agent is Abbv-990,BAT-2022, NED-260, ALG-097431, bardoxolone, delcetravir, ESFAM-289,ENOB-CV-01, ENOB-CV-11, EIS-10700, beta-521, SIM-0417, molnupiravir,Pan-Corona, Tollovir, nirmatrelvir+ritonavir (Paxlovid*), favipiravir,GC-376, upamostat, LeSoleil-01, LeSoleil-02+, benfovir, VV-116, VV-993,SNB-01, EDP-235, Cov-X, ensitrelvir, MPI-8, masitinib, ALG-097558,ASC-11, PBI-0451, nafamostat, nafamostat mesylate, CDI-45205, COR-803,ALG-097111, BC-201, SH-879, CDI-873, CDI-988, remdesivir, NV-CoV-2-R,NV-CoV-1 encapsulated remdesivir, NA-831+remdesivir, DEP remdesivir,GS-621763, GS-5245, GLS-5310, bemnifosbuvir, QLS-1128, ASC-10, SBFM-PL4,camostat mesylate, UCI-1, FB-2001 (DC-402234), ebselen, SH-580,LeSoleil-01, LeSoleil-02+, MRX-18, MXB-9, MI-09, MI-30, SNB-02,SJP-002C, TJC-642, ENU-200, CVD-0013943, GS-441524, bepridil, MXB-004,eravacycline, GRL-0617, camostat, GC-373, nitazoxanide, cynarine,prexasertib, RAY-1216, SACT-COVID-19, MP-18, EIDD-1931, EDDC-2214,nitric oxide, apabetalone, AnQlar, SBK-001, LQ-050, CG-SpikeDown,bamlanivimab, HLX-71, HT-002, HY-209, HY-3000, FYB-207, ensovibep,SYZJ-001, EU-129, neumifil, JN-2019, AR-701, vostesyl, PLM-402, PJS-539,CTB-ACE2, TB181-36, TB202-3, ABP-300, XVR-011, MSP-008-22, MU-UNMC-1,MU-UNMC-2, alunacedase alfa, VP-01, TRV-027, DX-600, TXA-127,NVX-CoV2515, riamilovir, tozinameran, elasomeran, Ad5-nCoV, BBIBP-CorV,CoronaVac, MVC-COV1901, NVX-CoV2373, sotrovimab, Sputnik V, TEE-001,Tyme-19, Vaxzevria, ZF-2001, or ZyCoV-D.

X. Examples General Synthesis:

Scheme 1 shows the general synthesis of compounds of the presentinvention starting with the reaction of S1a and nucleoside S1b underbasic conditions (e.g., 4-dimethylaminopyridine (DMAP)) to afford S1c.LG represents a leaving group. Example leaving groups include, but arenot limited to, chloride, bromide, mesylate, tosylate, triflate,4-nitrobenzenesulfonate, 4-chlorobenzenesulfonate, 4-nitrophenoxy, andpentafluorophenoxy. This reaction is followed by acetonide cleavageunder acidic conditions (e.g., HCl) to afford the final compounds of thepresent invention of the type Sld.

Scheme 2 shows a general synthesis of compounds of the present inventionstarting with the reaction of nucleoside S1b with1,1′-carbonyldiimidazole (CDI) to generate intermediate S2a.Displacement of the imidazole with the alcohol S2b under basicconditions (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)) generatesthe penultimate intermediate S1c. The acetonide is then cleaved underacidic conditions (e.g., HCl) to afford the final compounds of thepresent invention of the type Sld.

Scheme 3 shows a general synthesis of compounds of the present inventionstarting with the addition of a protecting group (e.g.,dimethylformamidine) on N6 of nucleoside S1b to afford S3a. Reaction ofS3a with S1a under basic conditions (e.g., pyridine) generatesintermediate S3b, which is subsequently subjected to acidic conditions(e.g., HCl) to afford the final compounds of the present invention ofthe type Sld.

Scheme 4 shows a general synthesis of compounds of the present inventionstarting with the reaction of S1d with CDI or diphenyl carbonate toafford the final compounds of the present invention of the type S4a.

Scheme 5 shows a general synthesis of compounds of the present inventionstarting with the acetonide deprotection of S1b to generate thenucleoside S5a. Reaction of S5a with the anhydride S5b under basicconditions (e.g., DBU) affords the final compounds of the presentinvention of the type S1d.

Scheme 6a shows a general synthesis of compounds of the presentinvention starting with S1d. Reaction of S1d with a dicarbonate in thepresence DMAP in tetrahydrofuran (THF) affords the final compounds ofthe present invention of the type S6a-1 and S6a-2.

Scheme 7 describes the general synthesis of compounds of the presentinvention starting with S1d. Reacting compound S1d with chloromethyldisubstituted phosphate in the presence of sodium iodide in solvents(e.g., acetone) provides the intermediate S7a. PG is a protecting group.Example protecting groups include, but are not limited to,trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such asacetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl. Removal ofthe protecting group is achieved either by hydrogenation or treatmentwith an acid, which provides the compounds of the present invention ofthe type S7b.

Scheme 8 describes the general synthesis of N6-carbamates of the presentinvention like S8b starting with S1c. Reaction of S1c with acid chlorideunder basic conditions (like pyridine) generates intermediate S8a, whichis subsequently subjected to acidic conditions (e.g., HCl) to affordcompounds of the present invention of the type S8b.

Scheme 9 describes the general synthesis of N6-amide analogs of thepresent invention like S9b starting with S1c. Reaction of S1c with acidchloride

under basic conditions (like pyridine) generates intermediate S9a, whichis subsequently subjected to acidic conditions (e.g., HCl) to affordcompounds of the present invention of the type S9b.

Compounds of the present invention like S9b can also be obtained byreaction of S1c with corresponding acid. Reaction of S1c with acid

in the presence of1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (HATU) or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) to generateintermediate S9a, which is subsequently subjected to acidic conditions(e.g., HCl) to afford compounds of the present invention of the typeS9b.

Scheme 10 shows a general synthesis of compounds of the presentinvention starting with the reaction of diacids S10a with1,1′-carbonyldiimidazole to afford reagent S10b. Reaction between S10band nucleoside S1d can further afford the final compounds of the presentinvention of the type S10c.

Scheme 11 shows a general synthesis of compounds of the presentinvention starting with acylation of alcohols S11a with1,1′-carbonyldiimidazole (CDI) to afford reagent S11b. Reactions betweenS11b and S1b using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) generatesintermediate S1c. Reactions between S1c and S11c using pyridine as basefollowed by acidic treatment (e.g. HCl) then afford the final compoundsof the present invention of the type S11d.

Scheme 12 shows a general synthesis of acetalization of alcohols S1dwith propionaldehyde under acidic condition (e.g. PTSA) to afford thefinal compounds of the present invention of the type S12a.

Scheme 13 shows a general synthesis of esterification of alcohols S1dwith acid S13a using carbodiimide reaget (e.g. N,N′-diisopropylcarbodiimide (DIC)) and 4-dimethylaminopyridine (DMAP) toafford the final compounds of the present invention of the type S13b.

Scheme 14 shows a general synthesis of compounds of the presentinvention starting with the protecting group manipulation on the freeamine of nucleoside S1d to afford S14a.

Reactions of S14a with chloroformates S14b under basic conditions (e.g.pyridine) followed by acidic treatment (e.g. HCl) afford the finalcompounds of the present invention of the type S14c.

Synthesis of Intermediates Ia and Ib

To a solution of(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile,Intermediate I, (1000 mg, 3.0 mmol) (Siegel et. al. J. Med. Chem. 2017,60, 1648-1661) in DMF (5 mL), diisopropyl ethyl amine (780 mg, 6 mmol)was added followed by 4-dimethyl aminopyridine (369 mg, 3 mmol). To theabove solution at room temperature, isobutyl chloroformate (495 mg, 3.6mmol) was added and stirred for 1 h. LC-MS shows formation two products5′-carbonate and 5′-carbonate along with N6-carbamate. The reactionmixture was diluted with ethyl acetate (50 mL), washed with water,brine, dried over sodium sulfate and concentrated. The residue waspurified by flash chromatography using dichloromethane and methanol aseluants and separated the two products. Intermediate Ia:((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylisobutyl carbonate. LCMS: MS m/z: 432.1 (M+1). Intermediate Ib: isobutyl(7-((3aR,4R,6R,6aR)-4-cyano-6-(((isobutoxycarbonyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate.LCMS: MS m/z: 532.2 (M+1)

Synthesis of intermediate II

To a solution of(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile,Intermediate I, (3000 mg, 9.0 mmol) (Siegel et. al. J. Med. Chem. 2017,60, 1648-1661) in toluene (20 mL) N,N-Dimethylformamide dimethyl acetal(2158 mg, 18 mmol) was added and heated at 50° C. for 1 h. After thecompletion of the reaction, the solvent was evaporated under pressure,the residue was dissolved in ethyl acetate (100 mL). The solvent waswashed with water (10 mL) and brine (10 mL) dried over sodium sulphateand concentrated to get the intermediateN′-[7-[(3aR,4R,6R,6aR)-4-cyano-6-(hydroxymethyl)-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-N,N-dimethyl-formamidine,Intermediate II. LCMS: MS m/z: 387.2

Example 1:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylisobutyl carbonate (Compound 1)

To a solution of((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylisobutyl carbonate: Intermediate Ia (1300 mg, 3 mmol) in acetonitrile(10 mL), conc. HCl (1.3 mL, 15 mmol) was added and stirred at roomtemperature for 1 h. After the completion of the reaction, the reactionmixture was diluted with ethyl acetate (50 mL), neutralized withsaturated sodium bicarbonate, separated the organic layer, washed withwater, brine, dried and concentrated. The residue was purified by flashchromatography using dichloromethane and methanol as eluants to obtainthe title Compound 1. ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 2H), 6.90 (d,J=4.6 Hz, 1H), 6.79 (d, J=4.5 Hz, 1H), 6.32 (d, J=6.0 Hz, 1H), 5.40 (d,J=5.8 Hz, 1H), 4.67 (dd, J=6.1, 4.9 Hz, 1H), 4.46-4.36 (m, 1H),4.28-4.17 (m, 2H), 3.98-3.90 (m, 1H), 3.87 (d, J=6.5 Hz, 2H), 1.89 (dt,J=13.3, 6.7 Hz, 1H), 0.89 (d, J=6.7 Hz, 6H). LCMS: MS m/z: 392.1 (M+1)

Example 2: isobutyl(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(((isobutoxycarbonyl)oxy)methyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate(Compound 2)

To a solution of isobutyl(7-((3aR,4R,6R,6aR)-4-cyano-6-(((isobutoxycarbonyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamateIntermediate Ib (650 mg, 1.2 mmol) in acetonitrile (10 mL), conc. HCl(0.6 mL, 6 mmol) was added and stirred at room temperature for 1 h.After the completion of the reaction, the reaction mixture was dilutedwith ethyl acetate (50 mL), neutralized with saturated sodiumbicarbonate, separated the organic layer, washed with water, brine,dried and concentrated. The residue was purified by flash chromatographyusing dichloromethane and methanol as eluants to obtain Compound 2. ¹HNMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.37 (s, 1H), 7.31 (d, J=4.7 Hz,1H), 7.02 (d, J=4.7 Hz, 1H), 6.42 (d, J=6.0 Hz, 1H), 5.45 (d, J=5.9 Hz,1H), 4.66 (t, J=5.4 Hz, 1H), 4.42 (dd, J=11.6, 2.5 Hz, 1H), 4.34-4.13(m, 2H), 3.96 (dd, J=16.0, 6.2 Hz, 3H), 3.86 (d, J=6.5 Hz, 2H), 1.97(dq, J=13.6, 6.8 Hz, 1H), 1.88 (dt, J=13.3, 6.7 Hz, 1H), 0.96 (d, J=6.7Hz, 6H), 0.88 (d, J=6.7 Hz, 6H). LCMS: MS m/z: 492.2 (M+1)

Example 3:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylneopentyl carbonate (Compound 3)

To a solution of(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile,Intermediate I, (2000 mg, 6.0 mmol) in DMF (5 mL), diisopropylethylamine (1560 mg, 12 mmol) was added followed by 4-dimethylaminopyridine (737 mg, 6 mmol). To the above solution at roomtemperature, neopentyl chloroformate (1091 mg, 7.2 mmol) was added andstirred for 1 h. After the completion of the reaction, the reactionmixture was diluted with ethyl acetate (50 mL), washed with water,brine, dried over sodium sulfate and concentrated. The residue waspurified by flash chromatography using dichloromethane and methanol toprovide Intermediate 3a.

Intermediate 3a (2400 mg, 5.4 mmol) in acetonitrile (5 mL), was treatedwith conc. HCl (2.2 mL, 27 mmol) and stirred at r.t for 1 h. After thecompletion of the reaction, the reaction mixture was diluted with ethylacetate (50 mL), neutralized with saturated sodium bicarbonate, theorganic layer separated, washed with water, brine, dried andconcentrated. The residue was purified by flash chromatography usingdichloromethane and methanol as eluants to obtain Compound 3. ¹H NMR(400 MHz, DMSO-d6) δ 7.92 (s, 1H), 6.90 (d, J=4.5 Hz, 1H), 6.80 (d,J=4.5 Hz, 1H), 6.33 (d, J=6.0 Hz, 1H), 5.40 (d, J=5.8 Hz, 1H), 4.66 (dd,J=6.0, 4.9 Hz, 1H), 4.49-4.36 (m, 1H), 4.32-4.17 (m, 2H), 3.93 (ddd,J=8.8, 6.6, 4.4 Hz, 1H), 3.80 (d, J=1.7 Hz, 2H), 0.90 (s, 9H). LCMS: MSm/z: 406.2 (M+1).

Example 4:[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methylisopropyl carbonate (Compound 4)

To a solution of Intermediate II (850 mg, 2.2 mmol) in dichloromethane(20 mL), pyridine (1 mL) was added. The reaction mixture was cooled to0° C., and the isopropyl chloroformate (270 mg, 2.2 mmol) indichloromethane (5 mL) was slowly added, once the addition was complete,the cold bath was removed and stirred at room temperature for 1 h. Aftercompletion of the reaction, the reaction mixture was diluted withdichloromethane (50 mL), washed with water, brine and concentrated. Theresidue was purified by flash chromatography using ethyl acetate anddichloromethane as eluants to obtain the intermediate[(3aR,4R,6R,6aR)-4-cyano-4-[4-[(Z)-dimethylaminomethyleneamino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methylisopropyl carbonate (and/or its (E)-isomer), Intermediate 4a. LCMS: MSm/z: 473.2 (M+1).

Note that compounds such as Intermediate 4a can be E or Z isomers.Although the Z isomer is drawn throughout the disclosure, the E isomercan also be generated and isolated.

To a solution of the Intermediate 4a (1300 mg, 2.8 mmol) intetrahydrofuran (10 mL) cooled with an ice-bath, conc. HCl (1.3 mL, 43mmol) was added slowly and the reaction mixture stirred for 6-18 h.After completion of the reaction, the reaction mixture was diluted withethyl acetate (50 mL) and neutralized with saturated sodium bicarbonate.The organic layer was separated, washed with water, brine, andconcentrated. The residue was purified by flash chromatography usingdichloromethane and methanol as eluants to obtain the title compound,[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methylisopropyl carbonate, Compound 4. ¹H NMR (400 MHz, Acetonitrile-d3) δ7.94 (s, 1H), 6.84 (d, J=4.6 Hz, 1H), 6.78 (d, J=4.6 Hz, 1H), 6.33 (s,3H), 4.83-4.69 (m, 3H), 4.45-4.31 (m, 2H), 4.26-4.14 (m, 2H), 3.67 (d,J=5.1 Hz, 1H), 1.22 (t, J=6.7 Hz, 6H). LCMS: MS m/z: 378.1

Example 5:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylmethyl carbonate (Compound 5)

Compound 5 was synthesized as explained in Example 4 starting frommethyl chloroformate instead of isopropyl chloroformate.

Intermediate 5a:[(3aR,4R,6R,6aR)-4-cyano-4-[4-[(Z)-dimethylaminomethyleneamino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methylmethyl carbonate (and/or its (E)-isomer); LCMS: MS m/z=445.1 (M+1)

Compound 5: ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 6.91 (d, J=4.5 Hz,1H), 6.79 (d, J=4.5 Hz, 1H), 6.30 (d, J=6.1 Hz, 1H), 5.75 (s, OH), 5.40(d, J=5.8 Hz, 1H), 4.68 (dd, J=6.1, 4.9 Hz, 1H), 4.47-4.32 (m, 1H),4.30-4.16 (m, 2H), 3.94 (q, J=5.6 Hz, 1H), 3.70 (s, 3H). LCMS: MSm/z=350.1 (M+1)

Example 6:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylethyl carbonate (Compound 6)

Compound 6 was synthesized as explained in Example 4 starting from ethylchloroformate instead of isopropyl chloroformate.

Intermediate 6a:[(3aR,4R,6R,6aR)-4-cyano-4-[4-[(Z)-dimethylaminomethyleneamino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methylethyl carbonate (and/or its (E)-isomer). LCMS: MS m/z=459.2 (M+1)

Compound 6: ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.91 (d, J=4.5 Hz,1H), 6.79 (d, J=4.5 Hz, 1H), 6.30 (d, J=6.1 Hz, 1H), 5.40 (d, J=5.8 Hz,1H), 4.69 (dd, J=6.1, 5.0 Hz, 1H), 4.39 (dd, J=10.3, 4.1 Hz, 1H),4.29-4.17 (m, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.94 (q, J=5.8 Hz, 1H), 1.20(t, J=7.1 Hz, 3H). LCMS: MS m/z=363.9 (M+1)

Example 7:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylphenyl carbonate (Compound 7)

Compound 7 was synthesized as explained in Example 4 starting fromphenyl chloroformate instead of isopropyl chloroformate.

Intermediate 7a:[(3aR,4R,6R,6aR)-4-cyano-4-[4-[(Z)-dimethylaminomethyleneamino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methylphenyl carbonate (and/or its (E)-isomer). LCMS: MS m/z=507.1 (M+1)

Compound 7: ¹H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.48-7.37 (m, 2H),7.35-7.25 (m, 1H), 7.25-7.14 (m, 2H), 6.92 (d, J=4.5 Hz, 1H), 6.82 (d,J=4.5 Hz, 1H), 6.34 (d, J=6.1 Hz, 1H), 5.45 (d, J=5.7 Hz, 1H), 4.71 (dd,J=6.1, 4.9 Hz, 1H), 4.53 (dd, J=11.5, 2.6 Hz, 1H), 4.44-4.23 (m, 2H),4.01 (q, J=5.7 Hz, 1H). LCMS: MS m/z=412.1 (M+1)

Example 8:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylpropyl carbonate (Compound 8)

Compound 8 was synthesized as explained in Example 4 starting frompropyl chloroformate instead of isopropyl chloroformate.

Intermediate 8a:[(3aR,4R,6R,6aR)-4-cyano-4-[4-[(Z)-dimethylaminomethyleneamino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methylpropyl carbonate (and/or its (E)-isomer). LCMS: MS m/z=473.1 (M+1)

Compound 8: ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 6.90 (d, J=4.5 Hz,1H), 6.79 (d, J=4.5 Hz, 1H), 6.31 (d, J=6.1 Hz, 1H), 5.40 (d, J=5.8 Hz,1H), 4.68 (dd, J=6.1, 4.9 Hz, 1H), 4.50-4.30 (m, 1H), 4.30-4.14 (m, 2H),4.03 (t, J=6.6 Hz, 2H), 3.98-3.85 (m, 2H), 1.60 (dt, J=7.5, 6.6 Hz, 2H),0.88 (t, J=7.4 Hz, 3H). LCMS: MS m/z=378.1 (M+1)

Example 9:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclopropyl carbonate (Compound 9)

Compound 9 was synthesized as explained in Example 4 starting fromcyclopropyl chloroformate instead of isopropyl chloroformate.

Intermediate 9a:[(3aR,4R,6R,6aR)-4-cyano-4-[4-[(Z)-dimethylaminomethyleneamino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methylcyclopropyl carbonate (and/or its (E)-isomer). LCMS: MS m/z=471.1 (M+1)

Compound 9: ¹H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 6.91 (d, J=4.5 Hz,1H), 6.78 (d, J=4.5 Hz, 1H), 6.30 (d, J=6.1 Hz, 1H), 5.40 (d, J=5.7 Hz,1H), 4.68 (dd, J=6.1, 5.0 Hz, 1H), 4.50-4.31 (m, 1H), 4.29-4.16 (m, 2H),4.13-3.99 (m, 1H), 3.94 (q, J=5.5 Hz, 1H), 0.68 (m, 4H). LCMS: MSm/z=376.1 (M+1)

Example 10:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-methoxyethyl) carbonate (Compound 10)

The Compound 10 was synthesized as explained in Example 4 starting frommethoxy ethyl chloroformate instead of isopropyl chloroformate.

Intermediate 10a:[(3aR,4R,6R,6aR)-4-cyano-4-[4-[(Z)-dimethylaminomethyleneamino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl2-methoxyethyl carbonate (and/or its (E)-isomer). LCMS: MS m/z=489.3(M+1)

Compound 10: ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.91 (d, J=4.5Hz, 1H), 6.79 (d, J=4.5 Hz, 1H), 6.30 (d, J=6.1 Hz, 1H), 5.41 (d, J=5.7Hz, 1H), 4.69 (dd, J=6.1, 5.0 Hz, 1H), 4.47-4.35 (m, 1H), 4.30-4.13 (m,4H), 3.94 (q, J=5.5 Hz, 1H), 3.58-3.47 (m, 2H), 3.26 (s, 3H). LCMS: MSm/z=394.2 (M+1)

Example 11:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(tetrahydrofuran-3-yl) carbonate (Compound 11)

Compound 11 was synthesized as explained in Example 4 starting fromtetrahydrofuran-3-yl chloroformate instead of isopropyl chloroformate.

Intermediate 11a:[(3aR,4R,6R,6aR)-4-cyano-4-[4-[(Z)-dimethylaminomethyleneamino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyltetrahydrofuran-3-yl carbonate (and/or its (E)-isomer). LCMS: MSm/z=501.3 (M+1)

Compound 11: ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 6.92 (d, J=4.5Hz, 1H), 6.80 (dd, J=4.5, 1.3 Hz, 1H), 6.32 (d, J=6.1 Hz, 1H), 5.41 (d,J=5.7 Hz, 1H), 5.15 (ddt, J=5.9, 3.7, 1.7 Hz, 1H), 4.70 (dd, J=6.1, 4.9Hz, 1H), 4.49-4.35 (m, 1H), 4.32-4.15 (m, 2H), 3.95 (q, J=4.9 Hz, 1H),3.85-3.65 (m, 5H), 2.25-2.03 (m, 1H), 2.02-1.86 (m, 1H). LCMS: MSm/z=406.1 (M+1)

Example 12:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclopentyl carbonate (Compound 12)

Compound 12 was synthesized as explained in Example 4 starting fromcyclopentyl chloroformate instead of isopropyl chloroformate.

Intermediate 12a:[(3aR,4R,6R,6aR)-4-cyano-4-[4-[(Z)-dimethylaminomethyleneamino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methylcyclopentyl carbonate (and/or its (E)-isomer). LCMS: MS m/z=499.3 (M+1)

Compound 12: ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 2H), 6.91 (d, J=4.5Hz, 1H), 6.78 (d, J=4.6 Hz, 1H), 6.31 (d, J=6.0 Hz, 1H), 5.39 (d, J=5.8Hz, 1H), 4.98 (tt, J=6.0, 2.4 Hz, 1H), 4.67 (dd, J=6.0, 4.9 Hz, 1H),4.49-4.32 (m, 1H), 4.29-4.11 (m, 2H), 3.93 (q, J=5.8 Hz, 1H), 1.95-1.71(m, 4H), 1.74-1.45 (m, 4H). LCMS: MS m/z=404.2 (M+1)

Example 13:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylbenzyl carbonate (Compound 13)

Compound 13 was synthesized as explained in Example 4 starting frombenzyl chloroformate instead of isopropyl chloroformate.

Intermediate 13a:[(3aR,4R,6R,6aR)-4-cyano-4-[4-[(Z)-dimethylaminomethyleneamino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methylbenzyl carbonate (and/or its (E)-isomer). LCMS: MS m/z=521.3 (M+1)

Compound 13: ¹H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.46-7.29 (m,5H), 6.90 (d, J=4.6 Hz, 1H), 6.78 (d, J=4.5 Hz, 1H), 6.31 (d, J=6.1 Hz,1H), 5.40 (d, J=5.7 Hz, 1H), 5.14 (s, 2H), 4.68 (dd, J=6.1, 4.9 Hz, 1H),4.51-4.37 (m, 1H), 4.34-4.17 (m, 2H), 3.94 (q, J=5.8 Hz, 1H). LCMS: MSm/z=426.2 (M+1)

Example 14:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14)

To a solution of triphosgene (393 mg, 1.3 mmol, 0.34 eq) indichloromethane (20 mL) at 0° C., cyclooctanol (500 m, 3.9 mmol, 1 eq)was added. To the solution triethylamine (395 mg, 3.9 mmol) in dissolvedin dichloromethane (5 mL) was added slowly at ice temperature. Thereaction mixture was removed from the ice bath after 10 min and stirredat room temperature for 2 h. LCMS shows formation of the productcyclooctanyl chloroformate. The reaction mixture was used directly inthe next step. LCMS: MS m/z=212.9 (M+Na)

A solution of Intermediate II (150 mg, 0.39 mmol) and pyridine (1 mL) indichloromethane was cooled to 0° C. To this solution, the cyclooctanylchloroformate reaction mixture was added and stirred at room temperaturefor 2 h. LCMS shows the formation of the product[(3aR,4R,6R,6aR)-4-cyano-4-[4-[(Z)-dimethylaminomethyleneamino]pyrrolo[2,1-f]][1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methylcyclooctyl carbonate (and/or its (E)-isomer), Intermediate 14a. Thereaction mixture was washed with water, brine and concentrated andpurified by flash chromatography using dichloromethane and ethyl acetateas eluants. LCMS: MS m/z=541.2 (M+1)

To a solution of[(3aR,4R,6R,6aR)-4-cyano-4-[4-[(Z)-dimethylaminomethyleneamino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methylcyclooctyl carbonate (and/or its (E)-isomer) 14a (190 mg, 0.35 mmol) inTHF (5 mL) at 0° C. Conc. HCl (0.2 mL) was added and stirred at roomtemperature for 18 h. LCMS shows the complete conversion to the titlecompound.

After completion of the reaction, the reaction mixture was diluted withethyl acetate (25 mL) and neutralized with saturated sodium bicarbonate.The organic layer was separated, washed with water, brine, andconcentrated. The residue was purified by flash chromatography usingdichloromethane and methanol as eluants to obtain Compound 14. ¹H NMR(400 MHz, DMSO-d6) δ 7.91 (s, 3H), 6.90 (d, J=4.5 Hz, 1H), 6.78 (d,J=4.6 Hz, 1H), 6.30 (d, J=6.0 Hz, 1H), 5.38 (d, J=5.8 Hz, 1H), 4.67(ddd, J=9.8, 7.1, 4.6 Hz, 2H), 4.45-4.34 (m, 1H), 4.29-4.11 (m, 2H),3.93 (q, J=5.8 Hz, 1H), 1.78-1.58 (m, 7H), 1.49 (dt, J=11.3, 7.4 Hz,8H). LCMS: MS m/z=446.2 (M+1)

Example 15:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-ethylbutyl) carbonate (Compound 15)

The bis(2-ethylbutyl) carbonate was synthesized using the conditionsdescribed for the preparation of cyclooctanyl chloroformate in Example14 starting with 2-ethyl butanol instead of cyclooctanol. LCMS: MSm/z=230.3

The Intermediate 15a was synthesized as explained in Example 14 usingthe bis(2-ethylbutyl) carbonate and Intermediate II to obtain theintermediate[(3aR,4R,6R,6aR)-4-cyano-4-[4-[(Z)-dimethylaminomethyleneamino]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methyl2-ethylbutyl carbonate (and/or its (E)-isomer), Intermediate 15a. LCMS:MS m/z=515.3 (M+1)

Compound 15 was synthesized as explained in Example 14 usingIntermediate 15a. Compound 15: ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H),6.90 (d, J=4.5 Hz, 1H), 6.79 (d, J=4.5 Hz, 1H), 6.32 (d, J=5.9 Hz, 1H),5.39 (d, J=5.7 Hz, 1H), 4.66 (t, J=5.5 Hz, 1H), 4.48-4.38 (m, 1H),4.30-4.17 (m, 2H), 4.01 (d, J=5.7 Hz, 2H), 3.93 (q, J=5.7 Hz, 1H), 1.49(p, J=6.2 Hz, 1H), 1.30 (p, J=7.3 Hz, 4H), 0.85 (t, J=7.5 Hz, 6H). LCMS:MS m/z=420.2 (M+1)

Example 16:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((isobutoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diylbis(2-methylpropanoate) (Compound 16)

To a solution of Compound 1 (150 mg, 0.38 mmol) in THE (10 mL)isobutyric anhydride (78 mg, 0.77 mmol) was added followed by dimethylaminopyridine (7 mg, 0.06 mmol). The reaction mixture was stirred atroom temperature for 30 min. After the completion of the reaction, themixture was concentrated and purified by flash chromatography usingdichloromethane and ethyl acetate as eluants to provide Compound 16. ¹HNMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.93 (d, J=4.6 Hz, 1H), 6.77 (d,J=4.6 Hz, 1H), 6.09 (d, J=5.8 Hz, 1H), 5.43 (dd, J=5.7, 4.1 Hz, 1H),4.61 (dt, J=4.9, 3.6 Hz, 1H), 4.46 (dd, J=12.1, 3.4 Hz, 1H), 4.34 (dd,J=12.1, 5.0 Hz, 1H), 3.90-3.77 (m, 2H), 2.61 (dp, J=11.8, 7.0 Hz, 2H),1.85 (hept, J=6.7 Hz, 1H), 1.15 (dd, J=8.1, 7.0 Hz, 6H), 1.10 (d, J=7.0Hz, 6H), 0.85 (d, J=6.7 Hz, 6H). LCMS: MS m/z=532.3 (M+1)

Example 17:((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylisobutyl carbonate (Compound 17)

To a solution of Compound 1 (100 mg, 0.26 mmol) in DMF (2 mL), diphenylcarbonate (66 mg, 0.31 mmol) and triethylamine (26 mg, 0.26 mmol) wereadded and heated at 100° C. for 2 h. LCMS shows the complete conversionto the product. The reaction mixture was diluted with ethyl acetate,washed with bicarbonate, water, brine, dried over sodium sulphate andconcentrated and purified by flash using dichloromethane and ethylacetate as eluants to provide Compound 17. ¹H NMR (400 MHz, DMSO-d6) δ8.04 (d, J=25.5 Hz, 2H), 7.96 (s, 1H), 6.97-6.89 (m, 2H), 5.98 (d, J=7.7Hz, 1H), 5.50 (dd, J=7.7, 3.9 Hz, 1H), 4.82 (dt, J=5.8, 3.8 Hz, 1H),4.43 (dd, J=12.0, 3.8 Hz, 1H), 4.28 (dd, J=12.0, 5.8 Hz, 1H), 3.81 (dd,J=6.6, 1.7 Hz, 2H), 1.83 (dt, J=13.4, 6.7 Hz, 2H), 0.84 (d, J=6.7 Hz,6H). LCMS: MS m/z=418.1 (M+1).

Example 18:((2R,3S,4R,5R)-5-(3-((((benzyloxy)(hydroxy)phosphoryl)oxy)methyl)-4-imino-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylneopentyl carbonate (Compound 18)

To a solution of Compound 3 (750 mg, 1.9 mmol) and sodium iodide (832mg, 5.6 mmol) in acetone (20 mL), dibenzyl chloromethyl phosphate (1813mg, 5.6 mmol) in acetone (5 mL) was added slowly and stirred at roomtemperature for 48 h. After completion of the reaction, the solventswere distilled off and charged the residue on flash column and elutedwith dichloromethane and methanol as eluants to obtain Compound 18. ¹HNMR (400 MHz, DMSO-d6) δ 8.38 (d, J=1.5 Hz, 1H), 7.46 (d, J=4.7 Hz, 1H),7.32 (d, J=4.1 Hz, 3H), 7.16 (d, J=4.5 Hz, 4H), 6.96 (d, J=4.8 Hz, 1H),5.66 (d, J=12.0 Hz, 2H), 5.17 (t, J=14.2 Hz, 1H), 4.81 (d, J=7.0 Hz,1H), 4.71 (d, J=7.1 Hz, 2H), 4.52 (d, J=4.8 Hz, 1H), 4.41 (dd, J=12.2,2.7 Hz, 1H), 4.34-4.26 (m, 1H), 4.19 (dd, J=12.1, 5.1 Hz, 1H), 3.92 (dd,J=6.8, 4.9 Hz, 1H), 3.76 (d, J=3.4 Hz, 2H), 0.86 (s, 9H). ³¹P NMR (162MHz, DMSO-d6) δ −1.89 (dt, J=15.2, 7.9 Hz). LCMS: MS m/z=606.1 (M+1)

Example 19:((2R,3S,4R,5R)-5-cyano-3,4-dihydroxy-5-(4-imino-3-((phosphonooxy)methyl)-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-7-yl)tetrahydrofuran-2-yl)methylneopentyl carbonate (Compound 19)

To a solution of Compound 18 (350 mg, 0.58 mmol) in ethanol, 5%Palladium on Carbon (30 mg) was added and stirred under hydrogen balloonfor 48 h. The reaction was stopped, filtered washing with ethyl acetate,and the filtrate was concentrated. The residue was purified by prep HPLCusing 0.1% TFA acetonitrile and 0.1% TFA water as eluants to obtainCompound 19 as a trifluoroacetate (TFA) salt. Compound 19: ¹H NMR (400MHz, DMSO-d6) δ 8.41 (s, 1H), 7.48 (d, J=4.8 Hz, 1H), 7.37-7.22 (m, 1H),6.97 (d, J=4.8 Hz, 1H), 5.62 (d, J=10.7 Hz, 2H), 4.88-4.65 (m, 1H), 4.56(d, J=4.8 Hz, 1H), 4.47-4.33 (m, 1H), 4.27 (ddd, J=7.3, 5.1, 2.6 Hz,1H), 4.18 (dd, J=12.1, 5.1 Hz, 1H), 3.83-3.65 (m, 2H), 0.86 (s, 9H); ³¹PNMR (162 MHz, DMSO-d6) δ −0.30 (t, J=10.6 Hz). LCMS: MS m/z=516.2 (M+1).

Example 20:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylazetidin-3-yl carbonate (Compound 20)

Compound 20 was synthesized as explained in Example 4 starting fromtert-butyl 3-((chlorocarbonyl)oxy)azetidine-1-carboxylate instead ofisopropyl chloroformate. After neutralization, the organic layer wasseparated, and the aqueous layer was concentrated and purified by prepHPLC using 0.1% TFA acetonitrile and 0.1% TFA water as eluants to obtainCompound 20 as TFA salt. Intermediate 20a: tert-butyl3-(((((3aR,4R,6R,6aR)-6-cyano-6-(4-(((Z)-(dimethylamino)methylene)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)carbonyl)oxy)azetidine-1-carboxylate.LCMS: MS m/z=586.3 (M+1). Compound 20: ¹H NMR (400 MHz, DMSO-d₆) δ 9.25(s, 1H), 9.02 (s, 1H), 8.03 (d, J=39.0 Hz, 1H), 7.94 (s, 1H), 6.97 (d,J=4.6 Hz, 1H), 6.83 (d, J=4.5 Hz, 1H), 5.18 (tt, J=6.9, 5.1 Hz, 1H),4.71 (d, J=5.0 Hz, 1H), 4.46-4.37 (m, 1H), 4.27 (td, J=6.7, 6.0, 3.1 Hz,6H), 3.98-3.91 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.34. LCMS: MSm/z=391.2 (M+1)

Example 21:[(2R,3S,4R,5R)-5-[4-(butanoylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methylisobutyl carbonate (Compound 21)

To a solution of butyric acid (490 mg, 5.6 mmol), and HATU (1767 mg, 4.6mmol) in DMF (5 mL), Intermediate Ia (2000 mg, 4.6 mmol) was addedfollowed by diisopropyl ethyl amine (599 mg, 4.6 mmol) and stirred atroom temperature for 48h. The reaction mixture was diluted with ethylacetate (100 mL), washed with water (5 mL) and brine (10 ml), dried, andconcentrated to get[(3aR,4R,6R,6aR)-4-[4-(butanoylamino)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-cyano-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methylisobutyl carbonate, Intermediate 21a. LCMS: MS m/z=502.2 (M+1).

To a solution of Intermediate 21a (1550 mg, 3.1 mmol) in acetonitrile(10 mL), conc. HCl (1.4 mL, 15 mmol) was added and stirred at roomtemperature for 1 h. After the completion of the reaction, the reactionmixture was diluted with ethyl acetate (100 mL), neutralized withsaturated sodium bicarbonate, separated the organic layer, washed withwater and brine, dried, and concentrated. The residue was purified byflash chromatography using dichloromethane and methanol as eluants toobtain Compound 21. ¹H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.39 (s,1H), 7.28 (d, J=4.8 Hz, 1H), 7.03 (d, J=4.7 Hz, 1H), 6.43 (d, J=6.0 Hz,1H), 5.45 (d, J=5.3 Hz, 1H), 4.66 (t, J=5.2 Hz, 1H), 4.43 (dd, J=11.7,2.4 Hz, 1H), 4.34-4.14 (m, 2H), 3.94 (d, J=5.6 Hz, 1H), 3.86 (d, J=6.5Hz, 2H), 3.14 (qd, J=7.4, 4.2 Hz, 2H), 1.88 (dt, J=13.3, 6.7 Hz, 1H),1.63 (p, J=7.3 Hz, 2H), 0.94 (t, J=7.4 Hz, 3H), 0.88 (d, J=6.7 Hz, 6H).LCMS: MS m/z=462.1 (M+1).

Example 22:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyltert-butyl carbonate (Compound 46)

Step 1: Intermediate22a—((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-If][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyltert-butyl carbonate

To a solution of(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxole-4-carbonitrile(Intermediate I, 3.0 g, 9.1 mmol) and di-tert-butyl dicarbonate (2.17 g,10 mmol) in THE (30 mL) was added catalytic DMAP and the reactionmixture was stirred for 1.5 h. The reaction mixture was thenconcentrated in vacuo and purified by flash chromatography usingdichloromethane and methanol as eluents to obtain Intermediate 22a.LCMS: MS m/z: 432.0 (M+1).

Step 2: Compound46—((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyltert-butyl carbonate

To a solution of((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyltert-butyl carbonate (Intermediate 22a, 3.2 g, 7.4 mmol) in THE (30 mL)at 0° C. was added conc. HCl (3.1 mL, 37 mmol). After ˜10 min, thereaction mixture was brought to room temperature and stirred for 6 h.

The reaction mixture was diluted with ethyl acetate, neutralized withsat aq. NaHCO₃ solution, and the organics were separated and washed withwater, brine, dried and concentrated in vacuo. The resulting residue waspurified by flash chromatography using dichloromethane and methanol aseluents to obtain Compound 46. ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 2H),6.91 (d, J=4.6 Hz, 1H), 6.79 (d, J=4.5 Hz, 1H), 6.30 (d, J=6.1 Hz, 1H),5.38 (d, J=5.8 Hz, 1H), 4.67 (dd, J=6.1, 5.0 Hz, 1H), 4.35 (dd, J=11.8,2.9 Hz, 1H), 4.20 (td, J=6.2, 2.8 Hz, 1H), 4.12 (dd, J=11.8, 6.0 Hz,1H), 3.92 (td, J=6.3, 5.1 Hz, 1H), 1.41 (s, 9H). LCMS: MS m/z: 392.0(M+1).

Example 23:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate (Compound 47)

Step 1: Intermediate 23a

1-Methylcyclohexanol (2 mL, 16.1 mmol) was added dropwise to a stirringsolution of 1,1′-carbonyldiimidazole (3.91 g, 24.1 mmol) in DCM (53 mL)at 0° C., then warmed to room temperature and stirred for 16 h. Thereaction mixture was transferred to a separatory funnel, washed withwater two times, dried over MgSO₄, and concentrated. Intermediate 23awas quantified using NMR and used without further purification.

Step 2: Intermediate 23b

Intermediate 23a (2.21 g, 10.6 mmol) and Intermediate I (3.2 g, 9.66mmol) were dissolved in MeCN (27 mL) at room temperature, then wassubsequently treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL,1.93 mmol). The resulting solution was stirred at room temperature for16 h then was quenched with saturated aqueous ammonium chloride. Thebiphasic mixture was extracted using EtOAc three times, and the combinedorganic layers were dried over MgSO₄, concentrated. The crudeIntermediate 23b was used without further purification assumingquantitative yield. LCMS: MS m/z 494.1 (M+23).

Step 3: Compound47—((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate

A solution of Intermediate 23b (3.62 g, 1 mmol) in THE (77 mL) at 0° C.was treated with conc. HCl (6 mL, 72.6 mmol), then reaction was warmedto RT and stirred for 6.5 h. The resulting mixture was basified withsaturated aqueous sodium bicarbonate, extracted with EtOAc three times,and the combined organic layers were dried over MgSO₄ then concentrated.The residue was purified by flash chromatography using dichloromethaneand methanol as eluants to obtain Compound 47. ¹H NMR (400 MHz, DMSO-d6)δ 8.17-7.68 (m, 3H), 7.04-6.87 (m, 1H), 6.85-6.78 (m, 1H), 6.40-6.27 (m,1H), 5.51-5.32 (m, 1H), 4.77-4.56 (m, 1H), 4.44-4.33 (m, 1H), 4.26-4.07(m, 2H), 3.99-3.88 (m, 1H), 2.04-1.92 (m, 2H), 1.55-1.13 (m, 11H). LCMS:MS m/z: 454.1 (M+23).

Example 24:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl) carbonate (Compound 48)

Compound 48 was synthesized in a manner similar to Compound 47(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate), replacing 1-methylcyclohexanol withfenchyl alcohol (racemic). ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H),6.90 (d, J=4.6 Hz, 1H), 6.85-6.76 (m, 1H), 6.36 (d, J=6.0 Hz, 1H), 5.40(d, J=5.8 Hz, 1H), 4.64 (dd, J=5.9, 4.8 Hz, 1H), 4.48-4.37 (m, 1H),4.32-4.20 (m, 2H), 4.16 (t, J=3.1 Hz, 1H), 3.99-3.86 (m, 1H), 1.72-1.53(m, 4H), 1.50-1.34 (m, 1H), 1.17 (dt, J=10.1, 2.1 Hz, 1H), 1.05 (s, 7H),0.71 (s, 3H). LCMS: MS m/z: 472.1 (M+1).

Example 25:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-(pyridin-4-yl)propan-2-yl) carbonate (Compound 49)

Compound 49(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-(pyridin-4-yl)propan-2-yl) carbonate) was synthesized in a mannersimilar to Compound 47(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate), replacing 1-methylcyclohexanol with2-(pyridin-4-yl)propan-2-ol. ¹H NMR (400 MHz, DMSO-d6) δ 8.53-8.42 (m,2H), 7.93 (s, 3H), 7.31-7.19 (m, 2H), 6.93 (d, J=4.5 Hz, 1H), 6.82 (d,J=4.5 Hz, 1H), 6.33 (d, J=6.1 Hz, 1H), 5.40 (d, J=5.7 Hz, 1H), 4.69 (dd,J=6.1, 5.0 Hz, 1H), 4.33 (dd, J=11.6, 2.7 Hz, 1H), 4.25-4.09 (m, 2H),3.97-3.86 (m, 1H), 1.69 (d, J=2.8 Hz, 6H). LCMS: MS m/z: 455.1 (M+1)

Example 26:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(tetrahydro-2H-pyran-4-yl) carbonate (Compound 50)

Compound 50 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with tetrahydro-2H-pyran-4-ol. ¹HNMR (400 MHz, DMSO-d₆) δ 7.93 (s, 3H), 6.92 (d, J=4.5 Hz, 1H), 6.80 (d,J=4.5 Hz, 1H), 6.34 (d, J=6.0 Hz, 1H), 5.42 (d, J=5.8 Hz, 1H), 4.79-4.65(m, 2H), 4.49-4.38 (m, 1H), 4.29-4.17 (m, 2H), 3.95 (q, J=5.9 Hz, 1H),3.78 (dq, J=12.5, 4.4 Hz, 2H), 3.45 (tdd, J=9.0, 4.5, 3.0 Hz, 2H),1.94-1.84 (m, 2H), 1.62-1.48 (m, 2H). LCMS: MS m/z: 420.01 (M+1).

Example 27:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) carbonate(Compound 51)

Compound 51 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with (+)-Borneol. The crudereaction mixture was concentrated in vacuo and resulting Intermediate27a was used directly in the deprotection step. LCMS: MS m/z: 567.3(M+1). Compound 51 was purified by silica gel chromatography (0-15%MeOH/DCM). ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.90 (d, J=4.5 Hz,1H), 6.79 (d, J=4.5 Hz, 1H), 6.35 (d, J=6.0 Hz, 1H), 5.41 (d, J=5.8 Hz,1H), 4.73 (ddd, J=9.9, 3.4, 1.9 Hz, 1H), 4.65 (dd, J=6.0, 4.9 Hz, 1H),4.45 (dd, J=11.4, 2.3 Hz, 1H), 4.27-4.16 (m, 2H), 3.94 (td, J=6.2, 4.9Hz, 1H), 2.34-2.21 (m, 1H), 1.82 (ddd, J=13.0, 9.2, 4.2 Hz, 1H),1.77-1.63 (m, 2H), 1.30 (tt, J=11.9, 2.8 Hz, 1H), 1.20 (ddd, J=11.3,9.2, 4.3 Hz, 1H), 0.99 (dd, J=13.7, 3.4 Hz, 1H), 0.87 (s, 3H), 0.85 (s,3H), 0.82 (s, 3H). LCMS: MS m/z: 471.98 (M+1).

Example 28:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(bicyclo[2.2.1]heptan-1-ylmethyl) carbonate (Compound 52)

Compound 52 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol withbicyclo[2.2.1]heptan-1-ylmethanol. The crude reaction mixture wasconcentrated in vacuo and the intermediate was used directly in thedeprotection step. LCMS: MS m/z: 444.10 (M+1). 1H NMR (400 MHz, DMSO-d6)δ 7.92 (s, 3H), 6.90 (d, J=4.6 Hz, 1H), 6.79 (d, J=4.6 Hz, 1H), 6.34 (d,J=6.0 Hz, 1H), 5.41 (d, J=5.8 Hz, 1H), 4.67 (dd, J=6.0, 4.9 Hz, 1H),4.42 (d, J=9.0 Hz, 1H), 4.28-4.17 (m, 4H), 3.94 (q, J=5.8 Hz, 1H), 2.19(dd, J=5.3, 3.6 Hz, 1H), 1.63-1.52 (m, 2H), 1.43 (tt, J=13.2, 3.1 Hz,2H), 1.31-1.12 (m, 6H).

Example 29:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(cyclobutylmethyl) carbonate (Compound 53)

Compound 53 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with cyclobutylmethanol. The crudereaction mixture was concentrated in vacuo and the intermediate was useddirectly in the deprotection step. LCMS: MS m/z: 404.10 (M+1). 1H NMR(400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.91 (d, J=4.6 Hz, 1H), 6.79 (d,J=4.5 Hz, 1H), 6.33 (s, 1H), 5.41 (s, 1H), 4.67 (t, J=3.5 Hz, 1H),4.46-4.35 (m, 1H), 4.26-4.17 (m, 2H), 4.05 (d, J=6.7 Hz, 2H), 3.93 (t,J=5.6 Hz, 1H), 2.64-2.52 (m, 1H), 2.06-1.94 (m, 2H), 1.90-1.79 (m, 2H),1.79-1.68 (m, 2H).

Example 30:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylspiro[3.3]heptan-2-yl carbonate (Compound 29)

Compound 29 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with spiro[3.3]heptan-2-ol. Thecrude reaction mixture was concentrated in vacuo and intermediate wasused directly in the deprotection step. LCMS: MS m/z: 430.10 (M+1). 1HNMR (400 MHz, DMSO-d6) δ 7.91 (s, 3H), 6.91 (d, J=4.5 Hz, 1H), 6.78 (d,J=4.5 Hz, 1H), 6.31 (d, J=6.1 Hz, 1H), 5.40 (d, J=5.7 Hz, 1H), 4.77-4.64(m, 2H), 4.44-4.33 (m, 1H), 4.28-4.11 (m, 2H), 3.93 (q, J=5.8 Hz, 1H),2.44-2.33 (m, 2H), 2.02-1.87 (m, 6H), 1.85-1.72 (m, 2H).

Example 31:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-methoxy-2-methylpropyl) carbonate (Compound 54)

Compound 54 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with 2-methoxy-2-methylpropan-1-ol.The crude reaction mixture was concentrated in vacuo and theintermediate was used directly in the deprotection step. LCMS: MS m/z:422.10 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.90 (d, J=4.5Hz, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.34 (d, J=6.0 Hz, 1H), 5.41 (d, J=5.8Hz, 1H), 4.67 (dd, J=6.1, 4.9 Hz, 1H), 4.47-4.37 (m, 1H), 4.27-4.18 (m,2H), 4.00 (d, J=1.0 Hz, 2H), 3.94 (q, J=5.7 Hz, 1H), 3.11 (s, 3H), 1.11(s, 6H).

Example 32:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcycloheptyl) carbonate (Compound 55)

Step 1: Intermediate 32a—1,1-methylcycloheptylIH-imidazole-1-carboxylate

A mixture of 1-methylcycloheptan-1-ol (0.272 mL, 1.95 mmol),1,1′-carbonyldiimidazole (474 mg, 2.92 mmol), and potassium hydroxide(5.47 mg, 0.0975 mmol) in toluene (10.0 mL) was heated to 60° C.overnight. The reaction mixture was then diluted with DCM and washedtwice with H₂O. The organic phase was dried over MgSO₄, filtered, andconcentrated in vacuo. Intermediate 32a was quantified using NMR andused without further purification.

Step 2: Compound55—((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcycloheptyl) carbonate

Compound 55((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcycloheptyl) carbonate was synthesized in a manner similar toSteps 2 and 3 of Example 23,((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate (Compound 47), replacing Intermediate 23awith Intermediate 32a. ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.90(d, J=4.6 Hz, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.32 (d, J=6.0 Hz, 1H), 5.39(d, J=5.9 Hz, 1H), 4.65 (dd, J=6.0, 4.9 Hz, 1H), 4.36 (dd, J=11.9, 2.9Hz, 1H), 4.20 (td, J=6.2, 2.8 Hz, 1H), 4.12 (dd, J=11.9, 5.7 Hz, 1H),3.92 (dt, J=6.9, 5.7 Hz, 1H), 2.01 (dt, J=15.0, 7.9 Hz, 2H), 1.79-1.60(m, 2H), 1.58-1.45 (m, 6H), 1.44 (s, 3H), 1.42-1.31 (m, 2H). LCMS: MSm/z: 446.1 (M+1).

Example 33:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclopentyl) carbonate (Compound 56)

Compound 56((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclopentyl) carbonate was synthesized in a manner similar toCompound 55((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcycloheptyl) carbonate, replacing 1-methylcycloheptan-1-ol with1-methylcyclopentan-1-ol. ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.90(d, J=4.5 Hz, 1H), 6.79 (d, J=4.5 Hz, 1H), 6.32 (d, J=6.0 Hz, 1H), 5.40(d, J=5.8 Hz, 1H), 4.66 (t, J=5.5 Hz, 1H), 4.36 (dd, J=11.8, 2.8 Hz,1H), 4.20 (td, J=6.2, 2.7 Hz, 1H), 4.13 (dd, J=11.8, 5.9 Hz, 1H), 3.92(q, J=5.8 Hz, 1H), 2.06-1.93 (m, 2H), 1.63 (ttd, J=13.5, 9.1, 8.4, 3.8Hz, 6H), 1.50 (s, 3H). LCMS: MS m/z: 418.1 (M+1).

Example 34:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclooctyl) carbonate (Compound 57)

Step 1: Intermediate 34a

A stirred solution of cyclooctanone (10.5 mL, 79.7 mL) in diethyl ether(181 mL) was cooled to 0° C. then treated with MeMgBr (3 M in diethylether, 79.7 mL, 239 mmol). The resulting solution was warmed slowly toroom temperature over 16 h before it was cooled to 0° C. and quenched bydropwise addition of saturated aqueous ammonium chloride solution. Theorganic layer was separated, and the aqueous layer was extracted threetimes with diethyl ether. The combined organic layers were dried overMgSO₄, concentrated, and the crude was purified by flash chromatographyusing hexanes and ethyl acetate as eluants to obtain1-methylcyclooctanol.

1-Methylcyclooctanol (3.0 g, 21.1 mmol) was added dropwise to a stirringsolution of 1,1′-carbonyldiimidazole (5.1 g, 31.6 mmol) in DCM (69 mL)at 0° C., then warmed to room temperature and stirred for 16 h. Thereaction mixture was transferred to a separatory funnel, washed withwater two times, dried over MgSO₄, and concentrated. Intermediate 34awas used without further purification.

Step 2: Intermediate 34b

A stirred solution of Reference Compound A (1.0 g, 3.43 mmol) andIntermediate 34a (1.78 g, 7.55 mmol) in DMF (17 mL) at room temperaturewas treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL, 0.69 mmol).The resulting solution was stirred at room temperature for 16 h then wasquenched with saturated aqueous ammonium chloride. The mixture wasextracted using 1:1 Hexanes:EtOAc three times, and the combined organiclayers were dried over MgSO₄, concentrated. Residual DMF was removed byazeotroping with heptanes. The resulting crude was purified by flashchromatography using dichloromethane and ethyl acetate as eluants togive Intermediate 34b. ¹H NMR (400 MHz, DMSO-d6) δ 8.18-7.92 (m, 3H),6.96 (d, J=4.6 Hz, 1H), 6.91 (d, J=4.6 Hz, 1H), 5.99 (d, J=7.7 Hz, 1H),5.47 (dd, J=7.6, 3.9 Hz, 1H), 4.85-4.75 (m, 1H), 4.33 (dd, J=12.0, 4.0Hz, 1H), 4.18 (dd, J=12.0, 5.9 Hz, 1H), 1.98 (q, J=9.7, 8.5 Hz, 2H),1.72 (dd, J=15.0, 7.8 Hz, 2H), 1.40 (s, 13H).

Step 3: Compound 57—((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclooctyl) carbonate

A stirred solution of Intermediate 34b (374 mg, 0.77 mmol) in THF (30.8mL) was cooled to 0° C. and treated with aqueous NaOH (616 mg, 15.4mmol, in 30.8 mL H₂O). After 30 minutes the reaction mixture wasacidified with saturated aqueous ammonium chloride, and the organiclayer was separated. The aqueous layer was extracted with EtOAc threetimes, the combined organic layers were dried over MgSO₄, andconcentrated. The resulting crude was purified by flash chromatographyusing dichloromethane and ethyl acetate as eluants to give Compound 57.¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 6.91 (d, J=4.6 Hz, 1H), 6.80(d, J=4.5 Hz, 1H), 6.33 (d, J=6.0 Hz, 1H), 4.65 (t, J=5.4 Hz, 1H), 4.35(dd, J=11.9, 2.9 Hz, 1H), 4.23-4.16 (m, 1H), 4.14-4.08 (m, 1H),3.94-3.88 (m, 1H), 2.09-1.98 (m, 2H), 1.75 (dt, J=13.9, 8.7 Hz, 2H),1.48 (d, J=40.7 Hz, 13H).

Example 35:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(((tert-butoxycarbonyl)oxy)methyl)-2-cyanotetrahydrofuran-3,4-diylbis(2-methylpropanoate) (Compound 58)

To a solution of[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyltert-butyl carbonate (Compound 46, 1.00 g, 2.56 mmol) in DCM was addedtriethylamine (2.79 mL, 20.4 mmol). The reaction mixture was cooled to0° C., and isobutyryl chloride was added dropwise in separate portionsuntil full conversion of starting material was observed (a total of 3.0equiv used). The reaction mixture was then concentrated in vacuo andpurified by flash chromatography using dichloromethane and ethyl acetateas eluants to obtain Compound 58. ¹H NMR (400 MHz, DMSO-d6) δ 8.14-7.95(m, 2H), 7.93 (s, 1H), 6.94 (d, J=4.6 Hz, 1H), 6.78 (d, J=4.6 Hz, 1H),6.08 (d, J=5.7 Hz, 1H), 5.40 (t, J=5.0 Hz, 1H), 4.57 (q, J=4.4 Hz, 1H),4.39 (dd, J=12.2, 3.5 Hz, 1H), 4.26 (dd, J=12.1, 5.2 Hz, 1H), 2.70-2.53(m, 2H), 1.36 (s, 9H), 1.22-1.02 (m, 12H). LCMS: MS m/z: 532.0 (M+1).

Example 36:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diylbis(2-methylpropanoate) (Compound 59)

To((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylisopropyl carbonate (Compound 4), (800 mg, 2.27 mmol) andN,N′-disuccinimidyl carbonate (133 mg, 0.52 mmol) in DCM (1 mL) wasadded 2-methylpropanoyl chloride (497 mg, 4.66 mmol) at 0° C. After 10minutes, the reaction was purified by silica gel chromatography (0-10%MeOH in DCM) to afford Compound 59. LCMS: MS m/z: 518.2 (M+1). ¹H NMR(400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.93 (d, J=4.6 Hz, 1H), 6.77 (d,J=4.6 Hz, 1H), 6.07 (d, J=5.8 Hz, 1H), 5.42 (dd, J=5.8, 4.1 Hz, 1H),4.72 (p, J=6.2 Hz, 1H), 4.59 (dt, J=5.0, 3.7 Hz, 1H), 4.45 (dd, J=12.1,3.5 Hz, 1H), 4.32 (dd, J=12.1, 5.1 Hz, 1H), 2.60 (ddq, J=13.9, 11.3, 7.0Hz, 2H), 1.22-1.12 (m, 12H), 1.10 (d, J=7.0 Hz, 6H).

Example 37:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-((((tert-pentyloxy)carbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldi-tert-pentyl bis(carbonate) (Compound 60)

Step 1: Intermediate 37a

2-Methyl-2-butanol (1.0 mL, 9.13 mmol) was added dropwise to a stirringsolution of 1,1′-carbonyldiimidazole (2.22 g, 13.7 mmol) in DCM (30 mL)at 0° C., then warmed to room temperature and stirred for 16 h. Thereaction mixture was transferred to a separatory funnel, washed withwater two times, dried over MgSO₄, and concentrated. Intermediate 37awas used without further purification.

Step 2: Compound 60

A stirred solution of Reference Compound A (210 mg, 0.721 mmol) andIntermediate 37a (657 mg, 3.6 mmol) in DMF (2 mL) at room temperaturewas treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (22 mg, 0.144 mmol).The resulting solution was stirred at room temperature for 16 h then wasquenched with saturated aqueous ammonium chloride. The mixture wasextracted using 1:1 Hexanes:EtOAc three times, and the combined organiclayers were dried over MgSO₄, concentrated. Residual DMF was removed byazeotroping with heptanes. The resulting crude was purified by flashchromatography using hexanes and ethyl acetate as eluants to giveCompound 60. ¹H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 3H), 7.25 (d, J=4.6Hz, 1H), 7.11 (d, J=4.6 Hz, 1H), 6.21 (d, J=5.9 Hz, 1H), 5.50 (t, J=5.9Hz, 1H), 4.93-4.73 (m, 1H), 4.70 (dd, J=12.3, 3.3 Hz, 1H), 4.56 (dd,J=12.3, 4.9 Hz, 1H), 2.18-1.85 (m, 6H), 1.71-1.66 (m, 12H), 1.64-1.61(m, 6H), 1.25-0.93 (m, 9H). LCMS: MS m/z 656.2 (M+23).

Example 38:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclohexyl carbonate (Compound 35)

Compound 35 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with cyclohexanol. ¹H NMR (400 MHz,DMSO-d6) δ 7.92 (s, 3H), 6.91 (d, J=4.5 Hz, 1H), 6.79 (d, J=4.5 Hz, 1H),6.33 (d, J=6.0 Hz, 1H), 5.41 (d, J=5.8 Hz, 1H), 4.67 (dd, J=6.0, 4.9 Hz,1H), 4.52 (ddt, J=12.7, 8.7, 3.8 Hz, 1H), 4.46-4.36 (m, 1H), 4.28-4.16(m, 2H), 3.93 (td, J=6.2, 4.9 Hz, 1H), 1.87-1.76 (m, 2H), 1.70-1.59 (m,2H), 1.52-1.15 (m, 6H). LCMS: MS m/z 418.0 (M+1).

Example 39: isopropyl(7-((2R,3R,4S,5R)-2-cyano-3-hydroxy-4-((isopropoxycarbonyl)oxy)-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate(Compound 62)

To a solution of((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylisopropyl carbonate, Compound 4 (1300 mg, 3.4 mmol) in dichloromethane(10 mL) was added pyridine (0.4 mL, 5.0 mmol). The mixture was thentreated with isopropyl chloroformate (8.5 mL, 1.0 M in toluene, 8.5mmol) and stirred at room temperature for 1 h. The reaction mixture wasdiluted with dichloromethane, washed with water, brine, dried over MgSO₄and concentrated. The residue was purified by flash chromatography usingdichloromethane and ethyl acetate as eluants to obtain Compound 62. ¹HNMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1H), 8.37 (s, 1H), 7.34 (s, 1H), 7.05(d, J=4.9 Hz, 1H), 6.85 (d, J=6.0 Hz, 1H), 5.05-4.95 (m, 3H), 4.84-4.71(m, 2H), 4.60-4.35 (m, 2H), 4.30-4.26 (m, 1H), 1.32-1.19 (m, 18H). LCMS:MS m/z: 550.02 (M+1).

Example 40: isopropyl(7-((2R,3R,4S,5R)-5-(((tert-butoxycarbonyl)oxy)methyl)-2-cyano-3,4-dihydroxytetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate(Compound 63)

To a solution of((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyltert-butyl carbonate (Intermediate 22a, 1.9 g, 4.6 mmol, 1 equiv) indichloromethane (16 mL) was added pyridine (0.56 mL, 6.9 mmol, 1.5equiv). The reaction mixture was cooled to 0° C. and isopropylchloroformate (5.5 mL of a 1N toluene solution, 5.5 mmol, 1.2 equiv) wasadded. The reaction mixture was slowly warmed to room temperature andstirred overnight. The reaction mixture was subsequently diluted withDCM/water, extracted twice with DCM, and the combined organics weredried over MgSO₄, filtered and concentrated in vacuo. The crude product,isopropyl(7-((3aR,4R,6R,6aR)-6-(((tert-butoxycarbonyl)oxy)methyl)-4-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate,was dissolved in THE (14 mL) and conc. HCl (1.9 mL, 23 mmol, 5.0 equiv)was added at 0° C. The reaction mixture was slowly warmed to roomtemperature and stirred for 5 hours before being quenched with sat. aq.NaHCO₃. The reaction mixture was diluted with EtOAc/water, extractedtwice with EtOAc, and the combined organics were dried over MgSO₄,filtered and concentrated in vacuo. The resulting product was purifiedusing silica gel chromatography (10-75% EtOAc/DCM). LCMS: MS m/z: 478.10(M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.36 (s, 1H), 7.32 (d,J=4.7 Hz, 1H), 7.00 (d, J=4.8 Hz, 1H), 6.41 (d, J=6.1 Hz, 1H), 5.44 (d,J=5.8 Hz, 1H), 4.98 (p, J=6.2 Hz, 1H), 4.65 (t, J=5.5 Hz, 1H), 4.36 (dd,J=11.9, 2.9 Hz, 1H), 4.23 (td, J=6.2, 2.8 Hz, 1H), 4.12 (dd, J=11.9, 5.7Hz, 1H), 3.92 (q, J=5.9 Hz, 1H), 1.40 (s, 9H), 1.31 (d, J=6.3 Hz, 6H).

The corresponding 5′ hydroxy compound, isopropyl(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate,was also isolated as a product from the deprotection reaction describedabove. LCMS: MS m/z: 378.10 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s,1H), 8.36 (s, 1H), 7.30 (d, J=4.8 Hz, 1H), 7.10 (d, J=4.8 Hz, 1H), 6.20(d, J=6.3 Hz, 1H), 5.23 (d, J=5.4 Hz, 1H), 4.98 (p, J=6.3 Hz, 1H), 4.89(t, J=5.6 Hz, 1H), 4.61 (t, J=5.6 Hz, 1H), 4.07 (dt, J=5.6, 3.9 Hz, 1H),3.95 (q, J=5.4 Hz, 1H), 3.71-3.58 (m, 1H), 3.51 (dt, J=12.2, 5.0 Hz,1H), 1.31 (d, J=6.3 Hz, 6H).

Example 41:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14; alternate synthesis)

Step 1: Intermediate 14a

To a mixture ofN′-(7-((3aR,4R,6R,6aR)-4-cyano-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-N,N-dimethylformimidamide,Intermediate II, (100 mg, 0.26 mmol) and N,N′-disuccinimidyl carbonate(133 mg, 0.52 mmol) in MeCN (1 mL) was added triethylamine (0.14 mL, 1.0mmol). The mixture was stirred for 3 h, after which cyclooctanol (0.21mL, 1.6 mmol) was added, and the mixture then stirred at rt for 1 h.After the completion of the reaction, the reaction mixture was dilutedwith ethyl acetate, washed with water, brine, dried over MgSO₄ andconcentrated. Intermediate 14a was used without further purification.LCMS: MS m/z: 541.0 (M+1).

Step 2: Compound 14—((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate

Intermediate 14a (140 mg, 0.26 mmol) was dissolved in THE (1.5 mL), andtreated with conc. HCl (0.43 mL, 5.2 mmol) and stirred at roomtemperature overnight. After the completion of the reaction, thereaction mixture was diluted with ethyl acetate, neutralized withsaturated sodium bicarbonate, the organic layer separated, washed withwater, brine, dried over MgSO₄, filtered, and concentrated. The residuewas purified by flash chromatography using dichloromethane and methanolas eluants to obtain Compound 14. ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s,3H), 6.90 (d, J=4.6 Hz, 1H), 6.78 (d, J=4.5 Hz, 1H), 6.32 (d, J=6.1 Hz,1H), 5.40 (d, J=5.8 Hz, 1H), 4.68 (ddd, J=10.9, 7.2, 4.6 Hz, 2H),4.45-4.36 (m, 1H), 4.25-4.13 (m, 2H), 3.98-3.89 (m, 1H), 1.83-1.38 (m,14H). LCMS: MS m/z: 446.0 (M+1).

Example 42: Allyl(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl)carbonate (Compound 64)

To a solution ofN′-[7-[(3aR,4R,6R,6aR)-4-cyano-6-(hydroxymethyl)-2,2-dimethyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-4-yl]pyrrolo[2,1-f][1,2,4]triazin-4-yl]-N,N-dimethyl-formamidine(Intermediate II, 150 mg, 0.39 mmol) in dichloromethane (10 mL), allylchloroformate (1170 mg, 9.7 mmol) followed by pyridine (0.78 mL, 9.7mmol), was added and the mixture stirred at room temperature overnight.Reaction mixture was diluted with dichloromethane, washed with water,then brine, and combined organics were dried over MgSO₄, filtered, andconcentrated in vacuo. The resulting residue was diluted with THE (2mL), cooled to 0° C., and conc. HCl (0.32 mL, 3.9 mmol) was added. Themixture was stirred overnight, allowing to warm to room temperature. Themixture was then diluted with ethyl acetate, neutralized with sat.NaHCO₃ aq. solution, organics were separated and washed with water,followed by brine. Organics dried over MgSO₄, filtered, and concentratedin vacuo. The residue was then purified by flash chromatography usingdichloromethane and methanol as eluents to obtain Compound 64. ¹H NMR(400 MHz, DMSO-d₆) δ 7.92 (s, 3H), 6.90 (d, J=4.6 Hz, 1H), 6.79 (d,J=4.5 Hz, 1H), 6.33 (d, J=6.1 Hz, 1H), 5.92 (ddt, J=17.2, 10.5, 5.5 Hz,1H), 5.42 (d, J=5.8 Hz, 1H), 5.37-5.20 (m, 2H), 4.68 (dd, J=6.1, 5.0 Hz,1H), 4.60 (dt, J=5.6, 1.4 Hz, 2H), 4.45-4.37 (m, 1H), 4.28-4.19 (m, 2H),3.94 (q, J=5.6 Hz, 1H). LCMS: MS m/z: 376.0 (M+1).

Example 43:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldiacetate (Compound 65)

To a mixture of((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylisopropyl carbonate, Compound 4, (200 mg, 0.53 mmol) and aceticanhydride (129 mg, 0.60 mmol) in THF (5 mL) was added4-dimethylaminopyridine (9.7 mg, 0.08 mmol). The mixture was stirred atrt for 30 minutes. After the completion of the reaction, the reactionmixture was diluted with ethyl acetate, washed with water, brine, driedover MgSO₄ and concentrated. The residue was purified by flashchromatography using dichloromethane and ethyl acetate as eluants toobtain Compound 65. ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (br, 1H), 7.99 (br,1H), 7.95 (s, 1H), 6.95 (d, J=4.6 Hz, 1H), 6.80 (d, J=4.6 Hz, 1H), 6.06(d, J=5.9 Hz, 1H), 5.39 (dd, J=5.9, 4.8 Hz, 1H), 4.73 (hept, J=6.3 Hz,1H), 4.60 (td, J=4.9, 3.2 Hz, 1H), 4.47 (dd, J=12.1, 3.3 Hz, 1H), 4.31(dd, J=12.2, 5.2 Hz, 1H), 2.12 (s, 6H), 1.21-1.18 (m, 6H). LCMS: MS m/z:462.03 (M+1).

Example 44:((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylisopropyl carbonate (Compound 66)

To a mixture of((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylisopropyl carbonate, Compound 4, (189 mg, 0.5 mmol) and diphenylcarbonate (129 mg, 0.60 mmol) in DMF (3.6 mL) was added triethylamine(0.07 mL, 0.5 mmol). The mixture was heated to 100° C. and stirred for 2h. After the completion of the reaction, the reaction mixture wasdiluted with ethyl acetate, washed with water, brine, dried over MgSO₄and concentrated. The residue was purified by flash chromatography usingdichloromethane and methanol as eluants to obtain Compound 66. ¹H NMR(400 MHz, DMSO-d₆) δ 8.10 (br, 1H), 8.03 (br, 1H), 7.98 (s, 1H),6.99-6.89 (m, 2H), 6.00 (d, J=7.7 Hz, 1H), 5.49 (dd, J=7.7, 3.9 Hz, 1H),4.83-4.80 (m, 1H), 4.74-4.68 (m, 1H), 4.42 (dd, J=12.0, 3.9 Hz, 1H),4.27 (dd, J=12.0, 5.7 Hz, 1H), 1.20 (d, J=6.2 Hz, 3H), 1.17 (d, J=6.2Hz, 3H). LCMS: MS m/z: 404.01 (M+1).

Example 45:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (Compound 67)

Compound 67 was synthesized in a manner similar to Example 23:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate (Compound 47), replacing1-methylcyclohexanol with 1,1,1-Trifluoro-2-methyl-2-propanol. 1H NMR(400 MHz, DMSO-d6) δ 7.92 (s, 1H), 6.90 (d, J=4.5 Hz, 1H), 6.78 (d,J=4.5 Hz, 1H), 6.35 (d, J=6.0 Hz, 1H), 5.42 (d, J=5.8 Hz, 1H), 4.67 (dd,J=6.1, 4.9 Hz, 1H), 4.51-4.40 (m, 1H), 4.27-4.18 (m, 2H), 3.94 (q, J=5.8Hz, 1H), 1.67-1.60 (m, 6H). LCMS: MS m/z: 446.1 (M+1).

Example 46:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2,3-dimethylbutan-2-yl) carbonate (Compound 68)

Compound 68 was synthesized in a manner similar to Example 23:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate (Compound 47), replacing1-methylcyclohexanol with 2,3-dimethyl-2-butanol. 1H NMR (400 MHz,DMSO-d6) δ 8.04-7.68 (m, 3H), 6.90 (d, J=4.6 Hz, 1H), 6.80 (d, J=4.5 Hz,1H), 6.33 (d, J=6.0 Hz, 1H), 5.39 (d, J=5.9 Hz, 1H), 4.64 (t, J=5.4 Hz,1H), 4.36 (dd, J=11.8, 2.8 Hz, 1H), 4.26-4.18 (m, 1H), 4.17-4.09 (m,1H), 3.91 (q, J=5.6 Hz, 1H), 2.20-2.03 (m, 1H), 1.35 (s, 6H), 0.86 (d,J=6.8 Hz, 6H). LCMS: MS m/z: 442.1 (M+23).

Example 47:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(3-methylpentan-3-yl) carbonate (Compound 69)

Compound 69 was synthesized in a manner similar to Example 23:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate (Compound 47), replacing1-methylcyclohexanol with 3-methyl-3-pentanol. 1H NMR (400 MHz, DMSO-d6)δ 8.08-7.77 (m, 3H), 6.91 (d, J=4.6 Hz, 1H), 6.81 (d, J=4.5 Hz, 1H),6.33 (d, J=6.0 Hz, 1H), 5.40 (d, J=5.8 Hz, 1H), 4.69-4.60 (m, 1H), 4.36(dd, J=11.7, 2.8 Hz, 1H), 4.21 (td, J=6.2, 2.7 Hz, 1H), 4.18-4.09 (m,1H), 3.95-3.88 (m, 1H), 1.93-1.61 (m, 4H), 1.33 (s, 3H), 0.85-0.74 (m,6H). LCMS: MS m/z: 442.1 (M+23).

Example 48:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyltert-pentyl carbonate (Compound 70)

Compound 70 was synthesized in a manner similar to Example 23:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate (Compound 47), replacing1-methylcyclohexanol with 2-methyl-2-butanol. 1H NMR (400 MHz, DMSO-d6)δ 8.01-7.74 (m, 3H), 6.90 (d, J=4.5 Hz, 1H), 6.79 (d, J=4.5 Hz, 1H),6.32 (d, J=6.0 Hz, 1H), 5.39 (d, J=5.8 Hz, 1H), 4.69-4.63 (m, 1H), 4.35(dd, J=11.8, 2.8 Hz, 1H), 4.20 (td, J=6.2, 2.8 Hz, 1H), 4.12 (dd,J=11.7, 5.9 Hz, 1H), 3.95-3.88 (m, 1H), 1.80-1.67 (m, 2H), 1.37 (s, 6H),0.83 (t, J=7.5 Hz, 3H). LCMS: MS m/z: 406.1 (M+1).

Example 49:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) carbonate (Compound 71)

Compound 71 was synthesized in a manner similar to Example 23:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate (Compound 47), replacing1-methylcyclohexanol with isoborneol. ¹H NMR (400 MHz, DMSO-d6) δ8.10-7.70 (m, 3H), 6.89 (dd, J=4.6, 1.0 Hz, 1H), 6.79 (dd, J=5.9, 4.5Hz, 1H), 6.36 (dd, J=5.9, 1.3 Hz, 1H), 5.39 (dd, J=5.9, 1.4 Hz, 1H),4.61 (ddd, J=5.9, 4.8, 3.0 Hz, 1H), 4.51-4.38 (m, 2H), 4.27-4.13 (m,2H), 3.97-3.87 (m, 1H), 1.83-1.57 (m, 4H), 1.51 (tt, J=10.2, 3.0 Hz,1H), 1.16-1.01 (m, 2H), 0.93 (d, J=3.7 Hz, 3H), 0.87-0.76 (m, 6H). LCMS:MS m/z: 472.1 (M+1).

Example 50:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(bicyclo[1.1.1]pentan-1-ylmethyl) carbonate (Compound 72)

Compound 72 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol withbicyclo[1.1.1]pentan-1-ylmethanol. The crude reaction mixture wasconcentrated in vacuo and the resulting intermediate was used directlyin the deprotection step. LCMS: MS m/z: 416.00 (M+1). 1H NMR (400 MHz,DMSO-d6) δ 7.93 (s, 3H), 6.92 (d, J=4.5 Hz, 1H), 6.80 (d, J=4.5 Hz, 1H),6.33 (s, 1H), 5.41 (s, 1H), 4.67 (d, J=4.8 Hz, 1H), 4.41 (dd, J=9.4, 4.6Hz, 1H), 4.27-4.18 (m, 2H), 4.02 (s, 2H), 3.97-3.90 (m, 1H), 2.49 (s,1H), 1.72 (s, 6H).

Example 51:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(3,3-difluorocyclobutyl) carbonate (Compound 73)

Compound 73 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with 3,3-difluorocyclobutan-1-ol.The crude reaction mixture was concentrated in vacuo and the resultingintermediate was used directly in the deprotection step. LCMS: MS m/z:425.90 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.91 (d, J=4.5Hz, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.33 (d, J=6.1 Hz, 1H), 5.43 (d, J=5.7Hz, 1H), 4.85 (dddd, J=12.2, 7.6, 4.7, 2.8 Hz, 1H), 4.70 (dd, J=6.1, 4.9Hz, 1H), 4.50-4.37 (m, 1H), 4.33-4.17 (m, 2H), 3.96 (q, J=5.6 Hz, 1H),3.06 (ddddd, J=19.3, 11.9, 7.4, 5.3, 2.5 Hz, 2H), 2.84-2.64 (m, 2H).

Example 52:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-isopropyl-4-methylcyclohex-3-en-1-yl) carbonate (Compound 74)

Compound 74 was synthesized in a manner similar to Example 32,((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcycloheptyl) carbonate (Compound 55), replacing1-methylcycloheptan-1-ol with 4-carvomenthenol. ¹H NMR (400 MHz,DMSO-d6) δ 7.91 (s, 3H), 6.90 (dd, J=4.5, 2.7 Hz, 1H), 6.78 (dd, J=4.5,3.4 Hz, 1H), 6.32 (d, J=6.0 Hz, 1H), 5.38 (dd, J=5.9, 1.0 Hz, 1H), 5.23(d, J=12.0 Hz, 1H), 4.64 (dt, J=7.6, 5.7 Hz, 1H), 4.38-4.25 (m, 1H),4.24-4.09 (m, 2H), 3.94-3.84 (m, 1H), 2.55 (q, J=6.9 Hz, 1H), 2.36-2.12(m, 3H), 1.87 (s, 2H), 1.68-1.55 (m, 4H), 0.89-0.78 (m, 6H). LCMS: MSm/z: 472.1 (M+1).

Example 53:(2R,3R,4R,5R)-2-cyano-2-(4-isobutyramidopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diylbis(2-methylpropanoate) (Compound 75)

Compound 75 was synthesized in a manner similar to Example 36:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diylbis(2-methylpropanoate) (Compound 59), using 4.0 eq of 2-methylpropanoylchloride instead of 2.1 eq. ¹H NMR (400 MHz, Chloroform-d) δ 7.97 (s,1H), 7.12 (br, 1H), 6.92 (d, J=4.7 Hz, 1H), 6.59 (d, J=4.7 Hz, 1H), 6.30(d, J=5.9 Hz, 1H), 5.59-5.50 (m, 1H), 4.93-4.81 (m, 1H), 4.66-4.61 (m,1H), 4.56-4.37 (m, 3H), 2.77-2.57 (m, 2H), 1.35-1.18 (m, 24H). LCMS:1.15 min, MS m/z: 588.2 (M+1).

Example 54:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1,1-difluoro-2-methylpropan-2-yl) carbonate (Compound 76)

Step 1: Intermediate 54a—1,1-difluoro-2-methylpropan-2-ol

To a mixture of 1,1-difluoropropan-2-one (0.172 mL, 2.13 mmol) indiethyl ether (2 mL) at −10° C. (brine bath) was added MeMgBr (3.00mol/L, 0.851 mL, 2.55 mmol) dropwise. The mixture was stirred overnight,allowing to warm to room temperature. The mixture was then diluted withdiethyl ether and quenched with 2 M HCl. Partitioned between water andether, layers separated, and aqueous phase extracted with additionalether. The combined organics were dried over MgSO₄, filtered, andconcentrated in vacuo. The resulting residue was used without furtherpurification.

Step 2: Compound 76

Compound 76 was synthesized in a manner similar to Example 23:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate (Compound 47), replacing1-methylcyclohexanol with 1,1-difluoro-2-methylpropan-2-ol (Intermediate54a). ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.91 (d, J=4.5 Hz, 1H),6.79 (d, J=4.5 Hz, 1H), 6.33 (d, J=6.0 Hz, 1H), 6.16 (t, J=55.5 Hz, 1H),5.42 (d, J=5.7 Hz, 1H), 4.68 (dd, J=6.1, 4.9 Hz, 1H), 4.45-4.37 (m, 1H),4.27-4.17 (m, 2H), 3.93 (q, J=5.7 Hz, 1H), 1.46 (d, J=1.7 Hz, 6H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −132.88-−133.31 (m). LCMS: MS m/z: 428.0 (M+1).

Example 55: Ethyl2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)oxy)-2-methylpropanoate(Compound 77)

Compound 77 was synthesized in a manner similar to Example 23:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate (Compound 47), replacing1-methylcyclohexanol with ethyl 2-hydroxy-2-methylpropanoate. ¹H NMR(400 MHz, DMSO-d₆) δ 7.93 (s, 3H), 6.92 (d, J=4.6 Hz, 1H), 6.81 (d,J=4.5 Hz, 1H), 6.35 (d, J=6.1 Hz, 1H), 5.43 (d, J=5.8 Hz, 1H), 4.75-4.67(m, 1H), 4.45-4.34 (m, 1H), 4.31-4.20 (m, 2H), 4.16-4.05 (m, 2H),3.96-3.89 (m, 1H), 1.51 (d, J=1.8 Hz, 6H), 1.14 (t, J=7.1 Hz, 3H). LCMS:0.68 min, MS m/z: 450.0 (M+1).

Example 56: methylO-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)-N,N-dimethyl-L-threoninate(Compound 78)

Step 1: methyl dimethyl-L-threoninate

A vigorously stirred solution of L-threonine methyl ester hydrochloride(2 g, 11.8 mmol) in DCM:H₂O (2:1, 50 mL) was treated with potassiumcarbonate at room temperature. After continued stirring for 15 min, thetwo layers were separated, and the aqueous layer was extracted with DCM(30 mL×2). Combined organic layers were dried over magnesium sulfate andconcentrated gently. The resulting free amine was dissolved in MeOH (20mL), then formaldehyde (37 wt % in water, 5.3 mL, 70.8 mmol) and Pd/C (5wt %, 3.02 g, 1.42 mmol) was added. The reaction apparatus wasbackfilled with H₂ then stirred vigorously for 72 h at room temperature.The reaction mixture was filtered over celite, and the filtrate wasconcentrated gently. The crude was purified by flash chromatographyusing EtOAc and hexanes as eluants to afford desired tertiary amine.

Step 2: (2R,3S)-3-(dimethylamino)-4-methoxy-4-oxobutan-2-yl1H-imidazole-1-carboxylate

A stirred solution of 1,1′-carbonyldiimidazole (691 mg, 4.26 mmol) inDCM (9.5 mL) was treated with tertiary amine (458 mg, 2.84 mmol). Theresulting solution was stirred for 16 h at room temperature, then wastransferred to separatory funnel and washed with H2O (10 mL×2). Theorganic layer was dried over magnesium sulfate and concentrated. Theresulting crude carbamate was used directly without furtherpurification.

Step 3: methylO-((((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)carbonyl)-N,N-dimethyl-L-threoninate

A stirred solution of nucleoside (700 mg, 2.11 mmol) and carbamate (593mg, 2.32 mmol) in acetonitrile (7 mL) was treated with1,8-Diazabicyclo[5.4.0]undec-7-ene (0.06 mL, 0.423 mmol) at roomtemperature, then was left to stir for 16 h. The resulting solution wasquenched with saturated aqueous ammonium chloride (10 mL) then wasextracted with EtOAc (20 mL×3). The combined organic layers were driedover magnesium sulfate and concentrated. The resulting crude carbonatewas used directly without further purification.

Step 4: Compound 78—methylO-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)-N,N-dimethyl-L-threoninate

A stirred solution of carbonate (652 mg, 1.26 mmol) in THE (13 mL) wastreated with conc. HCl (1.04 mL, 12.6 mmol) at room temperature. Theresulting solution was stirred for 2 h then was quenched with saturatedsodium bicarbonate until no gas evolution. The mixture was extractedwith EtOAc (25 mL×3), the combined organic layers were dried overmagnesium sulfate and concentrated. The resulting crude was purified byThe crude was purified by flash chromatography using dichloromethane andmethanol as eluants to afford final 5′ carbonate nucleoside analogueCompound 78. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.90 (d, J=4.5Hz, 1H), 6.78 (d, J=4.5 Hz, 1H), 6.33 (d, J=5.9 Hz, 1H), 5.39 (d, J=5.8Hz, 1H), 5.03-4.93 (m, 1H), 4.70-4.63 (m, 1H), 4.42 (d, J=10.1 Hz, 1H),4.32-4.17 (m, 2H), 3.98-3.87 (m, 1H), 3.64 (s, 3H), 2.23 (s, 6H), 1.20(d, J=6.3 Hz, 3H). LCMS: MS m/z: 479.1 (M+1).

Example 57:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((((2-(pyridin-4-yl)propan-2-yl)oxy)carbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldiacetate (Compound 79)

Compound 79 was synthesized in a manner similar to(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldiacetate (Compound 65), replacing((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylisopropyl carbonate (Compound 4) with((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-(pyridin-4-yl)propan-2-yl) carbonate (Compound 49). ¹H NMR (400 MHz,DMSO-d₆) δ 8.49-8.42 (m, 2H), 8.07 (br, 1H), 8.00 (br, 1H), 7.96 (s,1H), 7.26-7.20 (m, 2H), 6.97 (d, J=4.6 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H),6.09 (d, J=6.0 Hz, 1H), 5.40 (dd, J=6.0, 4.8 Hz, 1H), 4.57 (td, J=5.0,3.2 Hz, 1H), 4.41 (dd, J=12.2, 3.2 Hz, 1H), 4.25 (dd, J=12.2, 5.1 Hz,1H), 2.13 (s, 3H), 2.12 (s, 3H), 1.68 (s, 3H), 1.64 (s, 3H). LCMS: MSm/z: 539.02 (M+1).

Example 58: tert-butyl(7-((2R,3R,4R,5R)-2-cyano-3,4-bis((isopropoxycarbonyl)oxy)-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate(Compound 80)

Step 1: Intermediate 58a

To a solution of(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile,Reference Compound A, (1000 mg, 3.4 mmol) in dichloromethane (20 mL) wasadded triethylamine (7.7 mL, 55 mmol). The mixture was stirred for 30minutes, after which tert-butyldimethylsilyl trifluoromethanesulfonate(9.5 mL, 41 mmol) was added, and the mixture then stirred at rt for 12hours. After the completion of the reaction, the reaction mixture wasdiluted with dichloromethane, washed with 4N HCl aqueous solution,brine, dried over MgSO₄ and concentrated. The reaction mixture wasconcentrated and purified by flash chromatography using hexanes andethyl acetate as eluants to obtain Intermediate 58a. ¹H NMR (400 MHz,DMSO-d₆) δ 7.94 (br, 2H), 7.86 (s, 1H), 6.95-6.85 (m, 2H), 5.44 (d,J=4.5 Hz, 1H), 4.29 (dd, J=4.5, 1.5 Hz, 1H), 4.17-4.08 (m, 1H), 4.03(dd, J=10.8, 8.0 Hz, 1H), 3.71 (dd, J=10.9, 5.0 Hz, 1H), 0.94 (s, 9H),0.90 (s, 9H), 0.76 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H),0.07 (s, 3H), −0.14 (s, 3H), −0.54 (s, 3H). LCMS: MS m/z: 634.23 (M+1).

Step 2: Intermediate 58c

To the mixture of Intermediate 58a (1000 mg, 1.6 mmol) and Boc anhydride(350 mg, 1.6 mmol) in THE (16 mL) was added triethylamine (0.23 mL, 1.6mmol) followed by 4-dimethylaminopyridine (98 mg, 0.8 mmol). Thereaction mixture was stirred at r.t for 12 hours and then was dilutedwith ethyl acetate, washed with water, brine, dried over MgSO₄,filtered, and concentrated. Intermediate 58b was directly dissolved inTHE (1.2 mL) and treated with tetra-n-butylammonium fluoride (0.74 mL,1.0M in THF, 0.74 mmol) and stirred at r.t for 1 hour. After thecompletion of the reaction, the reaction mixture was concentrated andpurified by flash chromatography using dichloromethane and methanol aseluants to obtain Intermediate 58c. ¹H NMR (400 MHz, DMSO-d6)¹H NMR (400MHz, DMSO-d6) δ 10.61 (s, 1H), 8.33 (s, 1H), 7.27 (s, 1H), 7.09 (s, 1H),6.20 (d, J=6.4 Hz, 1H), 5.24 (d, J=5.5 Hz, 1H), 4.91 (t, J=5.7 Hz, 1H),4.66-4.51 (m, 1H), 4.11-4.02 (m, 1H), 4.00-3.92 (m, 1H), 3.70-3.61 (m,1H), 3.56-3.47 (m, 1H), 1.53 (s, 9H). LCMS: MS m/z: 391.788 (M+1).

Step 3: Compound 80

To a solution of Intermediate 58c (50 mg, 0.13 mmol) in dichloromethane(1 mL) was added pyridine (0.05 mL, 0.64 mmol). The mixture was thenadded isopropyl chloroformate (0.52 mL, 1.0 M in toluene, 0.52 mmol) andstirred at room temperature for 3 h. The reaction mixture was dilutedwith dichloromethane, washed with water, brine, dried over MgSO₄ andconcentrated. The residue was purified by flash chromatography usingdichloromethane and ethyl acetate as eluants to obtain Compound 80. ¹HNMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H), 8.35 (s, 1H), 7.33 (s, 1H), 7.02(s, 1H), 5.96 (d, J=6.1 Hz, 1H), 5.39-5.28 (m, 1H), 4.87-4.59 (m, 4H),4.48 (dd, J=12.2, 3.4 Hz, 1H), 4.34 (dd, J=12.0, 4.8 Hz, 1H), 1.53 (s,9H), 1.31-1.09 (m, 18H). LCMS: MS m/z: 649.80 (M+1).

Example 59:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldiisopropyl bis(carbonate) (Compound 81)

To Compound 80 (57 mg, 0.09 mmol) was added 4N HCl in dioxane (0.76 mL,3.1 mmol). The reaction mixture was stirred at room temperatureovernight. The reaction mixture was diluted with ethyl acetate,neutralized with saturated sodium bicarbonate, the organic layerseparated, washed with water, brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography usingdichloromethane and ethyl acetate as eluants to obtain Compound 81. ¹HNMR (400 MHz, DMSO-d₆) δ 8.07 (br, 1H), 8.00 (br, 1H), 7.94 (s, 1H),6.95 (d, J=4.6 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H), 5.99 (d, J=6.0 Hz, 1H),5.33 (dd, J=6.0, 5.0 Hz, 1H), 4.86-4.66 (m, 3H), 4.61 (td, J=5.0, 3.2Hz, 1H), 4.48 (dd, J=12.2, 3.3 Hz, 1H), 4.33 (dd, J=12.2, 5.1 Hz, 1H),1.30-1.16 (m, 18H). LCMS: MS m/z: 549.95 (M+1).

Example 60:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-isopropyl-5-methylphenyl) carbonate (Compound 82)

Compound 82 was synthesized in manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with 2-isopropyl-5-methylphenol. 1HNMR (400 MHz, DMSO-d6) δ 8.15-7.89 (m, 3H), 7.24 (d, J=7.9 Hz, 1H),7.10-7.05 (m, 1H), 6.95 (d, J=4.6 Hz, 1H), 6.91-6.90 (m, 1H), 6.85 (d,J=4.5 Hz, 1H), 6.39 (s, 1H), 5.47 (s, 1H), 4.70 (d, J=4.9 Hz, 1H),4.59-4.52 (m, 1H), 4.45-4.37 (m, 1H), 4.36-4.28 (m, 1H), 4.05-3.99 (m,1H), 2.98-2.88 (m, 1H), 2.27 (s, 3H), 1.10 (dd, J=6.9, 2.7 Hz, 6H).LCMS: 0.86 min, MS m/z: 468.0 (M+1).

Example 61:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl) carbonate (Compound 83)

Compound 83 was synthesized in manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with(1R,2S,5R)-2-isopropyl-5-methylcyclohexan-1-ol. ¹H NMR (400 MHz,DMSO-d₆) δ 8.05-7.86 (m, 3H), 6.91 (d, J=4.5 Hz, 1H), 6.78 (t, J=3.9 Hz,1H), 6.34 (s, 1H), 5.41 (s, 1H), 4.68-4.61 (m, 1H), 4.48-4.37 (m, 2H),4.27-4.17 (m, 2H), 3.97-3.90 (m, 1H), 2.00-1.77 (m, 2H), 1.68-1.57 (m,2H), 1.52-1.28 (m, 2H), 1.10-0.95 (m, 2H), 0.91-0.78 (m, 7H), 0.78-0.67(m, 3H). LCMS: 0.94 min, MS m/z: 474.0 (M+1).

Example 62:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(4,4-difluorocyclohexyl) carbonate (Compound 84)

Compound 84 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with 4,4-difluorocyclohexanol. ¹HNMR (400 MHz, DMSO-d6) δ 8.08-7.76 (m, 3H), 6.90 (d, J=4.5 Hz, 1H), 6.79(d, J=4.5 Hz, 1H), 6.34 (d, J=6.0 Hz, 1H), 5.41 (d, J=5.8 Hz, 1H), 4.76(tq, J=6.0, 2.7 Hz, 1H), 4.68 (dd, J=6.0, 4.9 Hz, 1H), 4.49-4.38 (m,1H), 4.29-4.16 (m, 2H), 3.94 (q, J=5.8 Hz, 1H), 2.04-1.82 (m, 6H),1.82-1.67 (m, 2H). LCMS: MS m/z 453.9 (M+1).

Example 63:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(cyclopentylmethyl) carbonate (Compound 85)

Compound 85 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with cyclopentylmethanol. ¹H NMR(400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.90 (d, J=4.5 Hz, 1H), 6.79 (d,J=4.5 Hz, 1H), 6.33 (d, J=6.0 Hz, 1H), 5.41 (d, J=5.7 Hz, 1H), 4.67 (dd,J=6.0, 4.9 Hz, 1H), 4.45-4.36 (m, 1H), 4.27-4.17 (m, 2H), 3.95 (dd,J=9.8, 6.3 Hz, 3H), 2.14 (h, J=7.5 Hz, 1H), 1.75-1.62 (m, 2H), 1.61-1.42(m, 4H), 1.21 (dq, J=11.0, 6.8 Hz, 2H). LCMS: MS m/z 418.0 (M+1).

Example 64:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(cyclohexylmethyl) carbonate (Compound 86)

Compound 86 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with cyclohexylmethanol. ¹H NMR(400 MHz, DMSO-d6) δ 8.03-7.75 (m, 3H), 6.90 (d, J=4.5 Hz, 1H), 6.79 (d,J=4.5 Hz, 1H), 6.33 (d, J=6.0 Hz, 1H), 5.41 (d, J=5.8 Hz, 1H), 4.67 (dd,J=6.0, 4.9 Hz, 1H), 4.47-4.34 (m, 1H), 4.28-4.14 (m, 2H), 3.93 (q, J=5.6Hz, 1H), 3.89 (d, J=6.3 Hz, 2H), 1.72-1.51 (m, 6H), 1.28-1.03 (m, 3H),1.00-0.82 (m, 2H). LCMS: MS m/z 432.0 (M+1).

Example 65:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-1-phenylethyl) carbonate (Compound 87)

Compound 87 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with (1R)-1-phenylethanol. ¹H NMR(400 MHz, DMSO-d6) δ 8.03-7.74 (m, 3H), 7.39-7.26 (m, 5H), 6.91 (d,J=4.5 Hz, 1H), 6.79 (d, J=4.5 Hz, 1H), 6.32 (d, J=6.0 Hz, 1H), 5.67 (q,J=6.5 Hz, 1H), 5.40 (d, J=5.8 Hz, 1H), 4.67 (dd, J=6.0, 4.9 Hz, 1H),4.43 (dd, J=11.4, 2.4 Hz, 1H), 4.27-4.13 (m, 2H), 3.92 (td, J=6.2, 5.0Hz, 1H), 1.51 (d, J=6.6 Hz, 3H). LCMS: MS m/z 439.9 (M+1).

Example 66:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((S)-1-phenylethyl) carbonate (Compound 88)

Compound 88 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with (1S)-1-phenylethanol. ¹H NMR(400 MHz, DMSO-d6) δ 8.04-7.79 (m, 3H), 7.41-7.25 (m, 5H), 6.91 (d,J=4.5 Hz, 1H), 6.77 (d, J=4.5 Hz, 1H), 6.32 (d, J=6.1 Hz, 1H), 5.67 (q,J=6.5 Hz, 1H), 5.40 (d, J=5.7 Hz, 1H), 4.67 (dd, J=6.1, 4.9 Hz, 1H),4.41-4.30 (m, 1H), 4.23 (dd, J=8.8, 5.8 Hz, 2H), 3.93 (q, J=5.6 Hz, 1H),1.50 (d, J=6.6 Hz, 3H). LCMS: MS m/z 440.0 (M+1).

Example 67:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((R)-sec-butyl) carbonate (Compound 89)

Compound 89 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with (2R)-butan-2-ol. ¹H NMR (400MHz, DMSO-d6) δ 8.02-7.75 (m, 3H), 6.90 (d, J=4.5 Hz, 1H), 6.78 (d,J=4.5 Hz, 1H), 6.32 (d, J=6.0 Hz, 1H), 5.40 (d, J=5.8 Hz, 1H), 4.67 (dd,J=6.0, 4.9 Hz, 1H), 4.59 (h, J=6.2 Hz, 1H), 4.46-4.34 (m, 1H), 4.26-4.15(m, 2H), 3.93 (q, J=5.8 Hz, 1H), 1.54 (dtd, J=13.3, 7.4, 3.0 Hz, 2H),1.19 (d, J=6.2 Hz, 3H), 0.84 (t, J=7.4 Hz, 3H). LCMS: MS m/z 392.0(M+1).

Example 68:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((S)-sec-butyl) carbonate (Compound 90)

Compound 90 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with (2S)-butan-2-ol. ¹H NMR (400MHz, DMSO-d6) δ 8.03-7.78 (m, 3H), 6.90 (d, J=4.5 Hz, 1H), 6.78 (d,J=4.5 Hz, 1H), 6.32 (d, J=6.0 Hz, 1H), 5.40 (d, J=5.8 Hz, 1H), 4.66 (dd,J=6.1, 4.9 Hz, 1H), 4.59 (p, J=6.2 Hz, 1H), 4.46-4.34 (m, 1H), 4.27-4.14(m, 2H), 3.93 (q, J=5.8 Hz, 1H), 1.61-1.47 (m, 2H), 1.19 (d, J=6.3 Hz,3H), 0.86 (t, J=7.5 Hz, 3H). LCMS: MS m/z 392.0 (M+1).

Example 69:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(pyrimidin-2-ylmethyl) carbonate (Compound 91)

Compound 69 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with pyrimidin-2-ylmethanol. ¹H NMR(400 MHz, DMSO-d6) δ 8.81 (d, J=4.9 Hz, 2H), 8.05-7.74 (m, 3H), 7.46 (t,J=4.9 Hz, 1H), 6.90 (d, J=4.5 Hz, 1H), 6.83 (d, J=4.5 Hz, 1H), 6.33 (d,J=6.1 Hz, 1H), 5.44 (d, J=5.7 Hz, 1H), 5.29 (s, 2H), 4.70 (dd, J=6.1,5.0 Hz, 1H), 4.50-4.36 (m, 1H), 4.33-4.19 (m, 2H), 3.97 (q, J=5.7 Hz,1H). LCMS: MS m/z 427.9 (M+1).

Example 70:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-morpholinoethyl) carbonate (Compound 92)

Compound 92 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with 4-(2-hydroxyethyl)morpholine.1H NMR (400 MHz, DMSO-d6) δ 8.06-7.78 (m, 3H), 6.90 (d, J=4.5 Hz, 1H),6.79 (d, J=4.5 Hz, 1H), 6.33 (d, J=6.0 Hz, 1H), 5.41 (d, J=5.7 Hz, 1H),4.69 (dd, J=6.1, 4.9 Hz, 1H), 4.44-4.36 (m, 2H), 4.27-4.20 (m, 2H),4.20-4.15 (m, 2H), 3.94 (q, J=5.6 Hz, 1H), 3.58-3.51 (m, 4H), 2.53 (t,J=5.6 Hz, 2H), 2.41-2.34 (m, 4H). LCMS: MS m/z: 449.1 (M+1).

Example 71:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((methoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldimethyl bis(carbonate) (Compound 93)

To a solution of Intermediate 58c (50 mg, 0.13 mmol) in dichloromethane(1 mL) was added pyridine (0.05 mL, 0.64 mmol). The mixture was thenadded methyl chloroformate (0.04 mL, 0.52 mmol) and stirred at roomtemperature for 3 h. The reaction mixture was diluted withdichloromethane, washed with water, brine, dried over MgSO₄ andconcentrated to afford Intermediate 71a. To the crude Intermediate 71awas added 4N HCl in dioxane (0.76 mL, 3.1 mmol). The reaction mixturewas stirred at room temperature overnight. The reaction mixture wasdiluted with ethyl acetate, neutralized with saturated sodiumbicarbonate, the organic layer separated, washed with water, brine,dried over MgSO₄, filtered, and concentrated. The residue was purifiedby flash chromatography using dichloromethane and ethyl acetate aseluants to obtain Compound 93. H NMR (400 MHz, DMSO-d₆) δ 8.07 (br, 1H),8.00 (br, 1H), 7.93 (s, 1H), 6.95 (d, J=4.6 Hz, 1H), 6.85 (d, J=4.6 Hz,1H), 6.05 (d, J=6.0 Hz, 1H), 5.38 (dd, J=6.0, 4.1 Hz, 1H), 4.71-4.63 (m,1H), 4.49 (dd, J=12.1, 3.3 Hz, 1H), 4.37 (dd, J=12.1, 5.0 Hz, 1H), 3.78(s, 3H), 3.77 (s, 3H), 3.69 (s, 3H). LCMS: MS m/z: 466.03 (M+1).

Example 72:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(3,3-dimethylcyclobutyl) carbonate (Compound 31)

Compound 31 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with 3,3-dimethylcyclobutan-1-ol.¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (s, 3H), 6.92 (d, J=4.6 Hz, 1H), 6.79(d, J=4.6 Hz, 1H), 6.32 (d, J=6.1 Hz, 1H), 5.41 (d, J=5.7 Hz, 1H),4.91-4.84 (m, 1H), 4.69 (dd, J=6.1, 4.9 Hz, 1H), 4.45-4.33 (m, 1H),4.27-4.15 (m, 2H), 3.94 (q, J=5.8 Hz, 1H), 2.23-2.11 (m, 2H), 1.87-1.77(m, 2H), 1.12 (m, 6H). LCMS: MS m/z: 418.02 (M+1).

Example 73:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1,3-difluoropropan-2-yl) carbonate (Compound 94)

Compound 94 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with 1,3-difluoropropan-2-ol. ¹HNMR (400 MHz, DMSO-d6) δ 7.93 (s, 3H), 6.92 (d, J=4.6 Hz, 1H), 6.80 (d,J=4.6 Hz, 1H), 6.35 (d, J=6.1 Hz, 1H), 5.44 (br, 1H), 5.20-5.07 (m, 1H),4.79-4.74 (m, 1H), 4.72-4.62 (m, 3H), 4.59-4.55 (m, 1H), 4.51-4.45 (m,1H), 4.34-4.22 (m, 2H), 3.96 (m, 1H). LCMS: MS m/z: 414.13 (M+1).

Example 74:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylpentyl carbonate (Compound 27)

Compound 27 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, using the 2-stepprocedure and replacing cyclooctanol with pentan-1-ol. ¹H NMR (400 MHz,DMSO-d₆) δ 7.93 (s, 3H), 6.91 (d, J=4.5 Hz, 1H), 6.80 (d, J=4.6 Hz, 1H),6.33 (d, J=6.1 Hz, 1H), 5.42 (d, J=5.8 Hz, 1H), 4.69 (dd, J=6.1, 5.0 Hz,1H), 4.53-4.31 (m, 1H), 4.29-4.14 (m, 2H), 4.07 (t, J=6.6 Hz, 2H), 3.94(q, J=5.8 Hz, 1H), 1.70-1.48 (m, 2H), 1.42-1.18 (m, 4H), 0.90-0.84 (m,3H). LCMS: MS m/z: 406.04 (M+1).

Example 75:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methoxy-2-methylpropan-2-yl) carbonate (Compound 96)

Compound 96 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate (Compound 47) in Example 23, replacing1-methylcyclohexanol with 1-methoxy-2-methyl-propan-2-ol. ¹H NMR (400MHz, DMSO-d₆) δ 7.94 (s, 3H), 6.92 (d, J=4.6 Hz, 1H), 6.81 (d, J=4.5 Hz,1H), 6.33 (d, J=6.0 Hz, 1H), 5.42 (d, J=5.8 Hz, 1H), 4.69 (t, J=5.5 Hz,1H), 4.37 (dd, J=11.7, 2.8 Hz, 1H), 4.22 (td, J=6.3, 2.8 Hz, 1H), 4.15(dd, J=11.7, 6.1 Hz, 1H), 3.94 (q, J=5.8 Hz, 1H), 3.44 (s, 2H), 3.28 (s,3H), 1.37 (s, 6H). LCMS: MS m/z: 421.90 (M+1).

Example 76: ethyl(S)-2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)oxy)propanoate(Compound 97)

Compound 97 was synthesized in a manner similar to Example 14:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14), replacing cyclooctanol with ethyl(S)-(−)-lactate. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s, 3H), 6.92 (d,J=4.5 Hz, 1H), 6.83 (d, J=4.5 Hz, 1H), 6.36 (d, J=5.5 Hz, 1H), 5.44 (d,J=5.7 Hz, 1H), 4.97 (q, J=7.0 Hz, 1H), 4.70 (t, J=5.2 Hz, 1H), 4.49-4.38(m, 1H), 4.33-4.21 (m, 2H), 4.16 (qd, J=7.2, 2.9 Hz, 2H), 3.93 (q, J=5.6Hz, 1H), 1.42 (d, J=7.0 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H). LCMS: MS m/z:436.04 (M+1).

Example 77:[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl[1-methyl-1-(2-pyridyl)ethyl] carbonate (Compound 98)

Compound 98 was synthesized in a manner similar to Example 23:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate (Compound 47), replacing1-methylcyclohexanol with 2-(2-pyridyl)propan-2-ol. 1H NMR (400 MHz,DMSO-d6) δ 8.52 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 8.03-7.85 (m, 3H), 7.75(td, J=7.8, 1.9 Hz, 1H), 7.38 (dt, J=8.0, 1.0 Hz, 1H), 7.28 (ddd, J=7.6,4.8, 1.1 Hz, 1H), 6.93 (d, J=4.6 Hz, 1H), 6.83 (d, J=4.5 Hz, 1H), 6.33(d, J=5.9 Hz, 1H), 5.41 (d, J=5.7 Hz, 1H), 4.69 (t, J=5.4 Hz, 1H), 4.32(dd, J=11.8, 2.8 Hz, 1H), 4.23-4.18 (m, 1H), 4.12 (dd, J=11.8, 6.0 Hz,1H), 3.93 (q, J=5.7 Hz, 1H), 1.71 (s, 6H). LCMS: MS m/z 455.1 (M+1).

Example 78:[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl[1-methyl-1-(3-pyridyl)ethyl] carbonate (Compound 99)

Compound 99 was synthesized in a manner similar to Example 23:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate (Compound 47), replacing1-methylcyclohexanol with 2-(3-pyridyl)propan-2-ol. 1H NMR (400 MHz,DMSO-d6) δ 8.61 (d, J=2.4 Hz, 1H), 8.55-8.46 (m, 1H), 8.03-7.82 (m, 3H),7.80-7.65 (m, 1H), 7.35 (dd, J=8.0, 4.7 Hz, 1H), 6.93 (d, J=4.6 Hz, 1H),6.81 (d, J=4.6 Hz, 1H), 6.32 (d, J=6.0 Hz, 1H), 5.40 (d, J=5.8 Hz, 1H),4.78-4.62 (m, 1H), 4.32 (dd, J=11.7, 2.8 Hz, 1H), 4.24-4.17 (m, 1H),4.13 (dd, J=11.7, 6.0 Hz, 1H), 3.92 (q, J=5.8 Hz, 1H), 1.75 (s, 6H).LCMS: MS m/z 455.1 (M+1).

Example 79:[(3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-cyano-2-phenyl-6,6a-dihydro-3aH-furo[3,4-d][1,3]dioxol-6-yl]methylisopropyl carbonate (Compound 100)

To a solution of[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methylisopropyl carbonate Compound 4 (100 mg, 0.27 mmol) and benzaldehyde (84mg, 0.8 mmol) in acetonitrile, Zinc chloride (36 mg, 0.27 mmol) wasadded and stirred at r.t for 18h. The reaction mixture was then dilutedwith ethyl acetate, washed with saturated NaHCO₃ and saturated brine.The organic layer was dried over Na₂SO₄, concentrated in vacuo andpurified by column chromatography eluting with ethyl acetate in hexane(0%-50%) to give desired product Compound 100. ¹H NMR (400 MHz, DMSO-d6)δ 7.96 (s, 3H), 7.69 (dd, J=6.8, 2.9 Hz, 2H), 7.47 (dd, J=5.0, 1.8 Hz,3H), 6.93 (dd, J=4.6, 0.8 Hz, 1H), 6.85 (d, J=4.5 Hz, 1H), 6.11 (s, 1H),5.55 (d, J=6.8 Hz, 1H), 5.04 (dd, J=6.8, 3.4 Hz, 1H), 4.69 (qd, J=7.4,6.3, 4.3 Hz, 2H), 4.32 (dd, J=11.8, 4.2 Hz, 1H), 4.18 (dd, J=11.8, 6.2Hz, 1H), 1.18 (dd, J=7.7, 6.3 Hz, 6H); LCMS: MS m/z: 466.2 (M+1)

Example 80:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) carbonate (Compound 26)

Compound 26 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one. ¹H NMR (400 MHz,DMSO-d₆) δ 7.92 (s, 3H), 6.91 (d, J=4.5 Hz, 1H), 6.79 (d, J=4.6 Hz, 1H),6.33 (d, J=6.1 Hz, 1H), 5.43 (d, J=5.7 Hz, 1H), 5.03 (s, 2H), 4.69 (t,J=5.5 Hz, 1H), 4.48-4.39 (m, 1H), 4.33-4.21 (m, 2H), 3.95 (q, J=5.6 Hz,1H), 2.17 (s, 3H). LCMS: MS m/z: 448.09 (M+1).

Example 81:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclobutyl carbonate (Compound 37)

Compound 37 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith cyclobutanol. ¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (s, 3H), 6.91 (d,J=4.5 Hz, 1H), 6.78 (d, J=4.6 Hz, 1H), 6.31 (d, J=6.1 Hz, 1H), 5.41 (d,J=5.7 Hz, 1H), 4.88-4.76 (m, 1H), 4.69 (dd, J=6.1, 4.9 Hz, 1H),4.42-4.33 (m, 1H), 4.25-4.12 (m, 2H), 3.94 (q, J=5.8 Hz, 1H), 2.32-2.20(m, 2H), 2.08-1.92 (m, 2H), 1.73 (ddddd, J=10.9, 9.9, 7.2, 2.7, 1.4 Hz,1H), 1.62-1.47 (m, 1H). LCMS: MS m/z: 390.00 (M+1)

Example 82:((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylmethyl carbonate (Compound 127)

Compound 127 was synthesized in a manner similar to((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylisopropyl carbonate (Compound 66) in Example 44, replacing((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylisopropyl carbonate (Compound 4) with((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylmethyl carbonate (Compound 5). ¹H NMR (400 MHz, DMSO-d6) δ 8.10 (br,1H), 8.03 (br, 1H), 7.98 (s, 1H), 6.96 (d, J=4.6 Hz, 1H), 6.92 (d, J=4.6Hz, 1H), 5.99 (d, J=7.8 Hz, 1H), 5.50 (dd, J=7.8, 4.0 Hz, 1H), 4.81 (dt,J=5.7, 4.0 Hz, 1H), 4.45 (dd, J=12.0, 3.8 Hz, 1H), 4.31 (dd, J=12.0, 5.7Hz, 1H), 3.67 (s, 3H). LCMS: MS m/z: 376.04 (M+1).

Example 83:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((methoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldiacetate (Compound 128)

Compound 128 was synthesized in a manner similar to(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldiacetate (Compound 65) in Example 43, replacing((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylisopropyl carbonate (Compound 4) with((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylmethyl carbonate (Compound 5). ¹H NMR (400 MHz, DMSO-d6) δ 8.04 (br,1H), 7.98 (br, 1H), 7.94 (s, 1H), 6.94 (d, J=4.6 Hz, 1H), 6.80 (d, J=4.6Hz, 1H), 6.07 (d, J=5.9 Hz, 1H), 5.41 (dd, J=5.9, 4.5 Hz, 1H), 4.61 (td,J=4.7, 3.2 Hz, 1H), 4.47 (dd, J=12.1, 3.2 Hz, 1H), 4.34 (dd, J=12.1, 5.0Hz, 1H), 3.68 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H). LCMS: MS m/z: 434.02(M+1).

Example 84:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((ethoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldiacetate (Compound 129)

Compound 129 was synthesized in a manner similar to(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldiacetate (Compound 65) in Example 43, replacing((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylisopropyl carbonate (Compound 4) with((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylethyl carbonate (Compound 6). ¹H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 3H),6.95 (d, J=4.7 Hz, 1H), 6.81 (d, J=4.6 Hz, 1H), 6.08 (d, J=5.9 Hz, 1H),5.41 (dd, J=6.0, 4.6 Hz, 1H), 4.61 (td, J=4.9, 3.2 Hz, 1H), 4.48 (dd,J=12.2, 3.2 Hz, 1H), 4.33 (dd, J=12.2, 5.1 Hz, 1H), 4.14-4.06 (m, 2H),2.12 (d, J=1.5 Hz, 6H), 1.19 (t, J=7.1 Hz, 3H). LCMS: MS m/z: 447.99(M+1).

Example 85:8-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-4-hydroxy-2-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-3-yl)oxy)-8-oxooctanoicacid (Compound 130)

To a stirring solution of suberic acid (2.0 g, 11 mmol) in THE (30 mL)was added 1,1′-carbonyldiimidazole (5.0 g, 31 mmol) at room temperature.The reaction mixture was stirred overnight. Intermediate 85a willprecipitate as white solid, which was then filtered and air dried.

To a suspension of Intermediate 85a (604 mg, 2.2 mmol) in anhydrous1,4-dioxane (100 mL) was added (Compound 4) (755 mg, 2.0 mmol) at roomtemperature with intense stirring. The catalysis of1,8-diazabicyclo[5.4.0]undec-7-ene (3 drops) was added to the reactionmedium, and the mixture was reacted at 80° C. for 15-20 hours. After thecompletion of the reaction, the reaction mixture was diluted with ethylacetate, washed with water, brine, dried over MgSO₄, and concentrated.The residue was purified by high-performance liquid chromatography usingwater and acetonitrile as eluants to obtain Compound 130. ¹H NMR (400MHz, DMSO-d₆) δ 11.98 (br, 1H), 7.93 (s, 3H), 6.93 (d, J=4.5 Hz, 1H),6.84 (d, J=4.6 Hz, 1H), 5.12 (t, J=5.1 Hz, 1H), 5.04 (d, J=5.6 Hz, 1H),4.78-4.69 (m, 1H), 4.46 (q, J=4.6 Hz, 1H), 4.39 (dd, J=12.0, 3.6 Hz,1H), 4.26 (dd, J=11.8, 5.6 Hz, 1H), 2.38 (t, J=7.3 Hz, 2H), 2.18 (t,J=7.4 Hz, 2H), 1.58 (t, J=7.4 Hz, 2H), 1.48 (q, J=7.2 Hz, 2H), 1.29 (dq,J=14.2, 8.3, 7.3 Hz, 4H), 1.21 (t, J=6.1 Hz, 6H). LCMS: MS m/z: 534.06(M+1).

Example 86: benzyl(7-((2R,3R,4S,5R)-2-cyano-5-(((ethoxycarbonyl)oxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate(Compound 131)

Ethanol (1.46 mL, 25 mmol) was added dropwise to a stirring solution of1,1′-carbonyldiimidazole (6.08 g, 37.5 mmol) in DCM (80 mL) at 0° C.,then warmed to room temperature and stirred for 16 h. The reactionmixture was transferred to a separatory funnel, washed with water twice,dried over MgSO₄, and concentrated. Intermediate 86a was used withoutfurther purification.

Intermediate 86a (1.40 g, 10.0 mmol) and S1b (3.0 g, 9.0 mmol) weredissolved in MeCN (27 mL) at room temperature, then was subsequentlytreated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL, 1.81 mmol).The resulting solution was stirred at room temperature for 16 h then wasquenched with saturated aqueous ammonium chloride. The biphasic mixturewas extracted using EtOAc three times, and the combined organic layerswere dried over MgSO₄ and concentrated. The crude Intermediate 86b wasused without further purification assuming quantitative yield.

To a solution of Intermediate 86b (4.0 g, 10 mmol) in DCM (100 mL) at 0°C. was added pyridine (2.46 mL, 30 mmol) followed by benzylchloroformate (6.1 mL, 18 mmol). The reaction mixture was warmed at RTand stirred overnight. The reaction mixture was then washed withsaturated aqueous sodium bicarbonate and the organic layer wasconcentrated. The crude product was then directly treated with 4N HCl in1,4-dioxane (24 mL) at RT overnight. The resulting mixture was thenbasified with saturated aqueous sodium bicarbonate and extracted withEtOAc three times. The combined organic layers were dried over MgSO₄then concentrated. The residue was purified by flash chromatographyusing dichloromethane and methanol as eluants to obtain Compound 131. ¹HNMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.39 (s, 1H), 7.51-7.46 (m, 2H),7.46-7.36 (m, 3H), 7.32 (d, J=4.5 Hz, 1H), 7.02 (d, J=4.8 Hz, 1H), 6.43(d, J=6.1 Hz, 1H), 5.46 (d, J=5.9 Hz, 1H), 5.27 (s, 2H), 4.67 (t, J=5.5Hz, 1H), 4.44-4.35 (m, 1H), 4.31-4.17 (m, 2H), 4.11 (q, J=7.1 Hz, 2H),3.94 (q, J=5.8 Hz, 1H), 1.19 (t, J=7.1 Hz, 3H). LCMS: MS m/z: 497.99(M+1).

Example 87:((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-ethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylethyl carbonate (Compound 132)

Propionaldehyde (1.6 mL, 22 mmol) and Compound 6 (1080 mg, 3.0 mmol)were added into DCM (30 mL). Under an ice bath, p-methylbenzenesulfonicacid (PTSA, 1131 mg, 2.0 mmol) was added to the reaction mixture andstir for 10 min. The reaction mixture was then warmed up to roomtemperature and was stirred overnight. The reaction solution was thenpoured into sat. NaHCO₃ solution and extracted with DCM. Ammonia ethanolsolution was added to the organic layer and concentrated resulting in acrude oil. The crude oil was then dissolved in ethyl acetate and washedwith brine. The organic layer was then dried and purified by flashchromatography using dichloromethane and methanol as eluants to obtainCompound 132. ¹H NMR (400 MHz, DMSO-d6) δ 8.01 (br, 2H), 7.95 (s, 1H),6.92 (d, J=4.6 Hz, 1H), 6.85 (d, J=4.6 Hz, 1H), 5.41 (d, J=6.5 Hz, 1H),5.17 (t, J=4.9 Hz, 1H), 4.87 (dd, J=6.6, 3.0 Hz, 1H), 4.59 (dt, J=6.9,3.8 Hz, 1H), 4.31 (dd, J=11.8, 4.1 Hz, 1H), 4.18 (dd, J=11.8, 5.9 Hz,1H), 4.06 (qd, J=7.1, 1.4 Hz, 2H), 1.86 (qd, J=7.5, 4.8 Hz, 2H), 1.16(t, J=7.1 Hz, 3H), 0.99 (t, J=7.5 Hz, 3H). LCMS: MS m/z: 403.98 (M+1).

Example 88:((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-ethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylisopropyl carbonate (Compound 133)

Compound 133 was synthesized in a manner similar to((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-ethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylethyl carbonate (Compound 132) in Example 87, replacing((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylethyl carbonate (Compound 6) with((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylisopropyl carbonate (Compound 4). ¹H NMR (400 MHz, DMSO-d6) δ 7.96 (s,3H), 6.92 (d, J=4.5 Hz, 1H), 6.84 (d, J=4.6 Hz, 1H), 5.40 (d, J=6.5 Hz,1H), 5.17 (t, J=4.9 Hz, 1H), 4.87 (dd, J=6.6, 3.0 Hz, 1H), 4.69 (hept,J=6.3 Hz, 1H), 4.59 (dt, J=6.7, 3.8 Hz, 1H), 4.29 (dd, J=11.8, 4.2 Hz,1H), 4.16 (dd, J=11.7, 6.1 Hz, 1H), 1.86 (qd, J=7.5, 4.8 Hz, 2H), 1.19(d, J=6.2 Hz, 3H), 1.17 (d, J=6.2 Hz, 3H), 0.99 (t, J=7.5 Hz, 3H). LCMS:MS m/z: 418.02 (M+1).

Example 89:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diylbis(pent-4-enoate) (Compound 134)

To a suspension of((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylisopropyl carbonate (Compound 4) (377 mg, 1.0 mmol) in DCM (5 mL) wasadded 4-pentenoic acid (200 mg, 2.0 mmol), N, N′-diisopropylcarbodiimide(DIC, 252 mg, 2.0 mmol) and 4-dimethylaminopyridine (61 mg, 0.5 mmol).The reaction was stirred at room temperature overnight. The reactionsolution was then poured into a sat. NaHCO₃ solution and extracted withDCM three times. The organic layers were then combined, dried,concentrated, and purified by flash chromatography using dichloromethaneand ethyl acetate as eluants to obtain Compound 134. ¹H NMR (400 MHz,DMSO-d6) δ 7.94 (s, 3H), 6.94 (d, J=4.6 Hz, 1H), 6.79 (d, J=4.6 Hz, 1H),6.11 (d, J=5.8 Hz, 1H), 5.82 (dddt, J=25.0, 16.7, 10.3, 6.3 Hz, 2H),5.43 (dd, J=5.9, 4.4 Hz, 1H), 5.14-4.91 (m, 4H), 4.73 (hept, J=6.3 Hz,1H), 4.60 (q, J=4.4 Hz, 1H), 4.46 (dd, J=12.2, 3.4 Hz, 1H), 4.31 (dd,J=12.1, 5.2 Hz, 1H), 2.61-2.51 (m, 2H), 2.50-2.42 (m, 2H), 2.41-2.24 (m,4H), 1.22-1.18 (m, 6H). LCMS: MS m/z: 542.07 (M+1).

Example 90:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldimethyl bis(carbonate) (Compound 135)

To a solution of((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylisopropyl carbonate (Compound 4) (1.1 g, 3.0 mmol) in dichloromethane(35 mL) was added triethylamine (4.2 mL, 30 mmol). The mixture wasstirred for 30 minutes, after which tert-butyldimethylsilyltrifluoromethanesulfonate (4.8 mL, 21 mmol) was added. The mixture thenstirred at rt for 12 hours. After the completion of the reaction, thereaction mixture was diluted with dichloromethane, washed with 4N HClaqueous solution and brine, dried over MgSO₄, and concentrated. Thecrude product was then dissolved in 30 mL of THF followed by theaddition of Boc anhydride (2.0 g, 9 mmol), triethylamine (2.1 mL, 15mmol), and 4-dimethylaminopyridine (367 mg, 3 mmol). The reactionmixture was stirred at r.t for 12 hours and then was diluted with ethylacetate, washed with water, brine, dried over MgSO₄, filtered, andconcentrated. The concentrated residue was then dissolved in THE (30mL), treated with tetra-n-butylammonium fluoride (13 mL, 1.0M in THF, 13mmol), and stirred at r.t for 3 hours. After the completion of thereaction, the reaction mixture was concentrated to obtain Intermediate90a. LCMS: MS m/z: 477.71 (M+1).

To a solution of Intermediate 90a (111 mg, 0.23 mmol) in dichloromethane(2 mL) was added pyridine (0.1 mL, 1.2 mmol). The mixture was then addedmethyl chloroformate (0.08 mL, 0.1 mmol) and stirred at room temperaturefor 3 h. The reaction mixture was diluted with dichloromethane, washedwith water, brine, dried over MgSO₄ and concentrated. To the residue wasthen added 4N HCl in dioxane (1 mL, 4 mmol). The reaction mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith ethyl acetate and neutralized with saturated sodium bicarbonate.The organic layer was separated, washed with water and brine, dried overMgSO₄, filtered, and concentrated. The resulting residue was purified byflash chromatography using dichloromethane and ethyl acetate as eluantsto obtain Compound 135. ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (br, 2H), 8.00(s, 1H), 6.95-6.93 (m, 1H) 6.89 (d, J=4.6 Hz, 1H), 6.27 (d, J=5.0 Hz,1H), 5.38 (dd, J=6.3, 5.0 Hz, 1H), 4.84-4.77 (m, 1H), 4.63 (td, J=5.5,3.0 Hz, 1H), 44.48 (dd, J=12.3, 3.0 Hz, 1H), 4.35-4.27 (m, 1H), 3.76 (s,3H), 3.71 (s, 3H), 1.28-1.20 (m, 6H). LCMS: MS m/z: 493.98 (M+1).

Example 91:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldi(but-3-en-1-yl) bis(carbonate) (Compound 136)

Compound 136 was synthesized in a manner similar to(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldimethyl bis(carbonate) (Compound 135) in Example 90, replacing methylchloroformate with 3-butenyl chloroformate. ¹H NMR (400 MHz, DMSO-d6) δ8.08 (br, 1H), 8.02 (br, 1H), 7.94 (s, 1H), 6.95 (d, J=4.6 Hz, 1H),6.90-6.87 (m, 1H), 5.92 (d, J=6.7 Hz, 1H), 5.48-5.36 (m, 3H), 4.73 (p,J=6.3 Hz, 1H), 4.56-4.44 (m, 4H), 4.28 (dd, J=12.3, 5.1 Hz, 1H), 4.10(dq, J=10.9, 5.9 Hz, 2H), 2.49-2.40 (m, 2H), 2.39-2.28 (m, 2H), 1.21 (d,J=6.2 Hz, 3H), 1.18 (d, J=6.2 Hz, 3H). LCMS: MS m/z: 546.02 (M+1).

Example 92:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((ethoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldiethyl bis(carbonate) (Compound 106)

Compound 106 was synthesized in a manner similar to Compound 81,replacing isopropyl chloroformate with ethyl chloroformate. ¹H NMR (400MHz, DMSO-d6) δ 8.07 (br, 1H), 8.00 (br, 1H), 7.93 (s, 1H), 6.95 (d,J=4.6 Hz, 1H), 6.84 (d, J=4.6 Hz, 1H), 6.03 (d, J=6.0 Hz, 1H), 5.36 (dd,J=6.0, 4.5 Hz, 1H), 4.65 (td, J=4.7, 3.3 Hz, 1H), 4.49 (dd, J=12.2, 3.3Hz, 1H), 4.35 (dd, J=12.2, 5.0 Hz, 1H), 4.18 (qd, J=7.1, 5.2 Hz, 4H),4.10 (qd, J=7.1, 1.9 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H), 1.23 (t, J=7.1 Hz,3H), 1.19 (t, J=7.1 Hz, 3H). LCMS: MS m/z: 507.96 (M+1).

Example 93:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(chloromethyl) carbonate (Compound 101)

Compound 101 was synthesized in a manner similar to Compound 4 inExample 4 starting from chloromethyl chloroformate instead of isopropylchloroformate. ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.91 (d, J=4.5Hz, 1H), 6.79 (d, J=4.5 Hz, 1H), 6.34 (d, J=6.1 Hz, 1H), 6.00-5.82 (m,2H), 5.44 (s, 1H), 4.69 (t, J=4.9 Hz, 1H), 4.52 (dd, J=11.9, 2.9 Hz,1H), 4.36 (dd, J=11.9, 5.9 Hz, 1H), 4.27 (td, J=6.2, 2.8 Hz, 1H), 3.95(t, J=5.9 Hz, 1H). LCMS: MS m/z=384.1 (M+1).

Example 94:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(((di-tert-butoxyphosphoryl)oxy)methyl) carbonate (Compound 110)

To a solution of Compound 101 (200 mg, 0.52 mmol) in THF (10 mL)tetrabutyl ammonium iodide (77 mg, 0.21 mmol) was added followed bypotassium ditert-butyl phosphate (259 mg, 1 mmol) and heated at 70° C.overnight. The reaction mixture was concentrated, diluted withdichloromethane, washed with water and brine, dried, and purified byprep HPLC using acetonitrile/Water as eluents to get the title Compound110. ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.91 (d, J=4.5 Hz, 1H),6.80 (d, J=4.5 Hz, 1H), 5.51 (d, J=13.6 Hz, 2H), 4.69 (t, J=5.0 Hz, 1H),4.45 (dd, J=11.9, 2.9 Hz, 1H), 4.38-4.20 (m, 2H), 4.03-3.89 (m, 1H),1.43-1.35 (m, 18H). LCMS: MS m/z=446.0 (M-112, deprotection).

Example 95:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((phosphonooxy)methyl) carbonate (Compound 40)

A solution of Compound 110 (100 mg, 0.18 mmol) in 10 mL of 10% TFA/DCMwas stirred at r.t for 2h. After completion of the starting material,the solvents were distilled off, and the residue was purified by prepHPLC using acetonitrile (0.1% TFA) and water (0.1% TFA) as eluents toget the title Compound 40 as a TFA salt. ¹H NMR (400 MHz, DMSO-d6) δ9.25-9.10 (m, 2H), 8.22 (dd, J=4.6, 1.4 Hz, 1H), 8.04 (d, J=4.6 Hz, 1H),6.67 (d, J=13.6 Hz, 2H), 5.87 (d, J=5.0 Hz, 1H), 5.67-5.57 (m, 1H),5.55-5.40 (m, 2H), 5.21-5.09 (m, 1H). LCMS: MS m/z=446.0 (M+1)

Example 96: methyl(7-((2R,3R,4R,5R)-2-cyano-3,4-bis((methoxycarbonyl)oxy)-5-((((neopentyloxy)carbonyl)oxy)methyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate(Compound 103)

To a solution of Compound 3 (100 mg, 0.25 mmol) in dichloromethane (10mL), methyl chloroformate (250 mg, 1.25 mml) was added followed bypyridine (0.1 mL). The resulting mixture was stirred at room temperaturefor 1 h. After completion of starting material, the mixture was dilutedwith DCM, washed with water, brine, concentrated, and purified by flashchromatography using EtOAc/DCM as eluents to get the title Compound 103.¹H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.38 (s, 1H), 7.35 (d, J=4.8Hz, 1H), 7.04 (d, J=4.8 Hz, 1H), 6.00 (d, J=5.8 Hz, 1H), 5.39 (dd,J=5.8, 4.2 Hz, 1H), 4.72 (td, J=4.6, 3.2 Hz, 1H), 4.50 (dd, J=12.2, 3.2Hz, 1H), 4.36 (dd, J=12.2, 4.9 Hz, 1H), 3.78 (d, J=2.8 Hz, 9H), 3.75 (s,2H), 0.86 (s, 9H). LCMS: MS m/z=522.1 (M+1).

Example 97:((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-cyano-2-methoxytetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methylisopropyl carbonate (Compound 107)

To a solution of Compound 4 (100 mg, 0.27 mmol) in dichloromethane (10mL), trimethyl orthoformate (84 mg, 0.87 mmol) was added followed byPPTS (67 mg, 0.27 mmol), and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was diluted withdichloromethane, washed with bicarbonate, water, and brine, dried, andpurified by flash chromatography using ethyl acetate and dichloromethaneas eluents. ¹H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 4H), 6.91 (d, J=4.5 Hz,1H), 6.79 (d, J=4.5 Hz, 1H), 6.15 (s, 1H), 5.40 (d, J=6.9 Hz, 1H), 5.04(dd, J=7.0, 4.8 Hz, 1H), 4.72 (p, J=6.3 Hz, 1H), 4.65 (dt, J=6.9, 4.5Hz, 1H), 4.29 (dd, J=11.8, 4.4 Hz, 1H), 4.11 (dd, J=11.8, 6.9 Hz, 1H),3.43 (s, 3H), 1.20 (dd, J=6.2, 2.4 Hz, 6H). LCMS: MS m/z=420.1 (M+1)

Example 98:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(cyclopropylmethyl) carbonate (Compound 125)

Compound 125 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith cyclopropylmethanol. ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.91(d, J=4.6 Hz, 1H), 6.79 (d, J=4.5 Hz, 1H), 6.32 (d, J=6.1 Hz, 1H), 5.41(d, J=5.7 Hz, 1H), 4.68 (dd, J=6.1, 5.0 Hz, 1H), 4.46-4.35 (m, 1H),4.28-4.14 (m, 2H), 3.93 (dd, J=9.9, 6.3 Hz, 3H), 1.18-1.03 (m, 1H),0.57-0.48 (m, 2H), 0.33-0.23 (m, 2H). LCMS: MS m/z: 390.0 (M+1).

Example 99:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((1-(trifluoromethyl)cyclopropyl)methyl) carbonate (Compound 120)

Compound 120 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith (1-(trifluoromethyl)cyclopropyl)methanol. ¹H NMR (400 MHz, DMSO-d6)δ 7.92 (s, 3H), 6.90 (d, J=4.5 Hz, 1H), 6.79 (d, J=4.6 Hz, 1H), 6.34 (d,J=6.0 Hz, 1H), 5.42 (d, J=5.8 Hz, 1H), 4.67 (dd, J=6.0, 4.9 Hz, 1H),4.48-4.39 (m, 1H), 4.31-4.20 (m, 4H), 3.93 (q, J=5.7 Hz, 1H), 1.10-1.04(m, 2H), 1.04-0.96 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ −68.66. LCMS:MS m/z: 457.90 (M+1).

Example 100.((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((3-cyanobicyclo[1.1.1]pentan-1-yl)methyl) carbonate (Compound 121)

Compound 121 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carbonitrile. ¹H NMR (400MHz, DMSO-d6) δ 7.93 (s, 3H), 6.92 (d, J=4.6 Hz, 1H), 6.80 (d, J=4.5 Hz,1H), 6.34 (s, 1H), 5.42 (s, 1H), 4.73-4.64 (m, 1H), 4.47-4.34 (m, 1H),4.29-4.15 (m, 2H), 4.08 (s, 2H), 3.93 (t, J=5.5 Hz, 1H), 2.20 (s, 6H).MS m/z: 440.97 (M+1)

Example 101:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(4-methoxyphenethyl) carbonate (Compound 112)

Compound 112 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith 2-(4-methoxyphenyl)ethan-1-ol. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s,3H), 7.56-7.03 (m, 2H), 6.93 (d, J=4.5 Hz, 1H), 6.89-6.83 (m, 2H), 6.80(d, J=4.5 Hz, 1H), 6.33 (d, J=6.1 Hz, 1H), 5.42 (d, J=5.8 Hz, 1H), 4.69(dd, J=6.1, 4.9 Hz, 1H), 4.38 (dd, J=9.8, 4.4 Hz, 1H), 4.23 (td, J=6.0,5.0, 3.5 Hz, 4H), 3.93 (q, J=5.8 Hz, 1H), 3.72 (s, 3H), 2.85 (t, J=6.8Hz, 2H). LCMS: MS m/z: 470.04 (M+1).

Example 102:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((1-methylcyclopropyl)methyl) carbonate (Compound 114)

Compound 114 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith (1-methylcyclopropyl)methanol. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s,3H), 6.92 (d, J=4.6 Hz, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.34 (d, J=6.0 Hz,1H), 5.42 (d, J=5.8 Hz, 1H), 4.69 (dd, J=6.0, 4.9 Hz, 1H), 4.48-4.37 (m,1H), 4.29-4.15 (m, 2H), 3.87-3.97 (m, 3H), 1.08 (s, 3H), 0.55-0.43 (m,2H), 0.43-0.26 (m, 2H). LCMS: MS m/z: 403.97 (M+1).

Example 103:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((3,3-difluorocyclobutyl)methyl) carbonate (Compound 115)

Compound 115 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith (3,3-difluorocyclobutyl)methanol. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93(s, 3H), 6.91 (d, J=4.5 Hz, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.34 (d, J=6.1Hz, 1H), 5.42 (d, J=5.8 Hz, 1H), 4.69 (dd, J=6.1, 4.9 Hz, 1H), 4.48-4.38(m, 1H), 4.29-4.19 (m, 2H), 4.15 (d, J=6.2 Hz, 2H), 3.95 (q, J=5.6 Hz,1H), 2.73-2.60 (m, 2H), 2.49-2.32 (m, 3H). LCMS: MS m/z: 440.06 (M+1).

Example 104:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((1-phenylcyclopropyl)methyl) carbonate (Compound 116)

Compound 116 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith (1-phenylcyclopropyl)methanol. ¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (s,3H), 7.30 (d, J=4.3 Hz, 4H), 7.20 (dt, J=8.6, 4.1 Hz, 1H), 6.92 (d,J=4.6 Hz, 1H), 6.78 (d, J=4.5 Hz, 1H), 6.32 (d, J=6.0 Hz, 1H), 5.40 (d,J=5.8 Hz, 1H), 4.67 (dd, J=6.1, 4.9 Hz, 1H), 4.42-4.31 (m, 1H),4.26-4.14 (m, 4H), 3.91 (q, J=5.7 Hz, 1H), 1.03-0.94 (m, 2H), 0.94-0.83(m, 2H). LCMS: MS m/z: 466.01 (M+1).

Example 105:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((3,3-dimethylcyclobutyl)methyl) carbonate (Compound 117)

Compound 117 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith (3,3-dimethylcyclobutyl)methanol. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93(s, 3H), 6.91 (d, J=4.6 Hz, 1H), 6.79 (d, J=4.6 Hz, 1H), 6.33 (d, J=6.1Hz, 1H), 5.41 (d, J=5.8 Hz, 1H), 4.68 (dd, J=6.1, 4.9 Hz, 1H), 4.46-4.35(m, 1H), 4.28-4.18 (m, 2H), 4.04 (d, J=6.7 Hz, 2H), 3.94 (q, J=5.8 Hz,1H), 2.50-2.44 (m, 1H), 1.82-1.71 (m, 2H), 1.57-1.52 (m, 2H), 1.12 (s,3H), 1.04 (s, 3H). LCMS: MS m/z: 432.02 (M+1).

Example 106:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((1-cyanocyclopropyl)methyl) carbonate (Compound 118)

Compound 118 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith 1-(hydroxymethyl)cyclopropane-1-carbonitrile. ¹H NMR (400 MHz,DMSO-d₆) δ 7.93 (s, 3H), 6.92 (d, J=4.5 Hz, 1H), 6.81 (d, J=4.5 Hz, 1H),6.34 (d, J=6.1 Hz, 1H), 5.44 (d, J=5.7 Hz, 1H), 4.71 (dd, J=6.1, 4.9 Hz,1H), 4.45 (dd, J=9.6, 5.1 Hz, 1H), 4.31-4.24 (m, 2H), 4.15 (s, 2H), 3.97(q, J=5.6 Hz, 1H), 1.39-1.32 (m, 2H), 1.22-1.13 (m, 2H). LCMS: MS m/z:415.11 (M+1).

Example 107:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((1-(cyanomethyl)cyclopropyl)methyl) carbonate (Compound 119)

Compound 119 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith 2-(1-(hydroxymethyl)cyclopropyl)acetonitrile. ¹H NMR (400 MHz,DMSO-d₆) δ 7.93 (s, 3H), 6.92 (d, J=4.5 Hz, 1H), 6.81 (d, J=4.5 Hz, 1H),6.34 (d, J=6.1 Hz, 1H), 5.43 (d, J=5.8 Hz, 1H), 4.69 (dd, J=6.1, 4.9 Hz,1H), 4.47-4.39 (m, 1H), 4.29-4.21 (m, 2H), 4.04 (s, 2H), 3.95 (q, J=5.6Hz, 1H), 2.68 (s, 2H), 0.73-0.66 (m, 2H), 0.66-0.59 (m, 2H). LCMS: MSm/z: 429.15 (M+1).

Example 108:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((1-methylcyclobutyl)methyl) carbonate (Compound 122)

Compound 122 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith (1-methylcyclobutyl)methanol. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s,3H), 6.91 (d, J=4.5 Hz, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.35 (d, J=6.0 Hz,1H), 5.42 (d, J=5.8 Hz, 1H), 4.67 (dd, J=6.0, 4.9 Hz, 1H), 4.49-4.39 (m,1H), 4.29-4.18 (m, 2H), 4.03-3.90 (m, 3H), 1.94-1.76 (m, 4H), 1.72-1.60(m, 2H), 1.11 (s, 3H). LCMS: MS m/z: 418.04 (M+1).

Example 109:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((1-methylcyclopentyl)methyl) carbonate (Compound 123)

Compound 123 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith (1-methylcyclopentyl)methanol. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93 (s,3H), 6.91 (d, J=4.5 Hz, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.35 (d, J=6.0 Hz,1H), 5.41 (d, J=5.8 Hz, 1H), 4.70-4.63 (m, 1H), 4.49-4.39 (m, 1H),4.29-4.18 (m, 2H), 4.00-3.84 (m, 3H), 1.63-1.56 (m, 4H), 1.51-1.44 (m,2H), 1.32-1.24 (m, 2H), 0.98 (s, 3H). LCMS: MS m/z: 432.06 (M+1).

Example 110: isopropyl(7-((2R,3R,4S,5R)-2-cyano-3,4-dihydroxy-5-(((isopropoxycarbonyl)oxy)methyl)tetrahydrofuran-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)carbamate(Compound 137)

To a solution of((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylisopropyl carbonate (Compound 4) (1300 mg, 3.4 mmol) in dichloromethane(10 mL) was added pyridine (0.4 mL, 5.0 mmol). To the mixture was addedisopropyl chloroformate (3.4 mL, 1.0 M in toluene, 3.4 mmol). Themixture stirred at room temperature for 1 h. The reaction mixture wasdiluted with dichloromethane, washed with water and brine, dried overMgSO₄, and concentrated. The residue was purified by flashchromatography using dichloromethane and ethyl acetate as eluants toobtain Compound 137. ¹H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.36 (s,1H), 7.42-7.20 (m, 1H), 7.00 (d, J=4.7 Hz, 1H), 6.43 (d, J=6.1 Hz, 1H),5.46 (d, J=5.8 Hz, 1H), 5.00-4.97 (m, 1H), 4.78-4.72 (m, 1H), 4.67 (dd,J=6.0, 4.9 Hz, 1H), 4.42 (dd, J=11.8, 2.6 Hz, 1H), 4.27 (td, J=6.2, 2.6Hz, 1H), 4.21 (dd, J=11.7, 5.8 Hz, 1H), 3.95 (q, J=5.8 Hz, 1H),1.32-1.21 (m, 12H). LCMS: MS m/z: 464.02 (M+1).

Example 111: tert-butyl2-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]-2-methyl-propanoate(Compound 138)

Compound 138 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate (Compound 47) in Example 23, replacing1-methylcyclohexanol with tert-butyl 2-hydroxy-2-methyl-propanoate andpurifying by flash column chromatography using C₁₈ column, and water andacetonitrile with 0.1% trifluoroacetic acid. ¹H NMR (400 MHz, DMSO-d6) δ8.81-8.30 (m, 2H), 8.06 (s, 1H), 7.14-7.02 (m, 1H), 6.96-6.83 (m, 1H),4.73-4.61 (m, 1H), 4.48-4.34 (m, 1H), 4.34-4.19 (m, 2H), 4.00-3.82 (m,1H), 3.45-3.28 (m, 1H), 1.55-1.29 (m, 15H). LCMS: MS m/z: 478.1 (M+1).

Example 112:[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]carbonate (Compound 139)

Compound 139 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate (Compound 47) in Example 23, replacing1-methylcyclohexanol with 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-oland purifying by flash column chromatography using dichloromethane andmethanol as eluents. ¹H NMR (400 MHz, DMSO-d6) δ 8.01-7.78 (m, 3H), 6.92(d, J=4.5 Hz, 1H), 6.78 (d, J=4.5 Hz, 1H), 6.34 (d, J=6.1 Hz, 1H), 5.43(d, J=5.7 Hz, 1H), 4.73-4.66 (m, 1H), 4.50-4.40 (m, 1H), 4.29-4.21 (m,2H), 3.96 (q, J=5.5 Hz, 1H), 2.41 (s, 6H). LCMS: MS m/z: 470.0 (M+1).

Example 113:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyldecyl carbonate (Compound 124)

Compound 124 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith 1-decanol. ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.91 (d, J=4.5Hz, 1H), 6.79 (d, J=4.5 Hz, 1H), 6.34 (d, J=6.0 Hz, 1H), 5.42 (d, J=5.8Hz, 1H), 4.68 (m, 1H), 4.46-4.35 (m, 1H), 4.28-4.17 (m, 2H), 4.07 (t,J=6.6 Hz, 2H), 3.93 (q, J=5.6 Hz, 1H), 1.58 (m, 2H), 1.25 (m, 16H),0.97-0.73 (m, 3H). LCMS: MS m/z 476.20 (M+1).

Example 114:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyloctadecyl carbonate (Compound 126)

Compound 126 was synthesized in a manner similar to((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methylcyclooctyl carbonate (Compound 14) in Example 41, replacing cyclooctanolwith 1-octadecanol. ¹H NMR (400 MHz, DMSO-d6) δ 8.04-7.74 (m, 3H), 6.90(d, J=4.5 Hz, 1H), 6.78 (d, J=4.5 Hz, 1H), 6.33 (d, J=6.0 Hz, 1H), 5.41(d, J=5.8 Hz, 1H), 4.67 (t, J=5.4 Hz, 1H), 4.44-4.35 (m, 1H), 4.27-4.18(m, 2H), 4.05 (t, J=6.6 Hz, 2H), 3.93 (q, J=5.7 Hz, 1H), 1.66-1.49 (m,2H), 1.32-1.14 (m, 32H), 0.91-0.78 (m, 3H).

Example 115:6-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)oxy)hexanoicacid (Compound 140)

tert-Butyl 6-hydroxyhexanoate (584 mg, 3.1 mmol) was added to a stirringsolution of 1,1′-carbonyldiimidazole (0.754 g, 4.65 mmol) in DCM (10 mL)at rt, and the reaction mixture was stirred for 16 h. The reactionmixture was then transferred to a separatory funnel, washed with watertwo times, dried over MgSO₄, and concentrated to afford Intermediate140a, which was directly used into next step without furtherpurification.

To the solution of Intermediate 140a (870 mg, 3.1 mmol) in MeCN (8 mL)was added Intermediate I (928 mg, 2.8 mmol) at room temperature followedby 1,8-diazabicyclo[5.4.0]undec-7-ene (85.3 mg, 0.56 mmol). Theresulting solution was stirred at room temperature for 16 h then wasquenched with saturated aqueous ammonium chloride. The biphasic mixturewas extracted using EtOAc three times, and the combined organic layerswere dried over MgSO₄, concentrated to afford Intermediate 140b, whichwas directly treated with 4N HCl in dioxane (14 mL) overnight. Thereaction mixture was then concentrated and purified by HPLC using(ACN+0.1% TFA/water+0.1% TFA) to afford Compound 140 as TFA salt. ¹H NMR(400 MHz, DMSO-d6) δ 11.99 (br, 1H), 8.49 (br, 1H), 8.27 (br, 1H), 8.02(s, 1H), 7.05 (s, 1H), 6.85 (d, J=4.6 Hz, 1H), 6.34 (br, 2H), 4.67 (d,J=4.9 Hz, 1H), 4.40 (d, J=9.8 Hz, 1H), 4.29-4.17 (m, 2H), 4.07 (t, J=6.6Hz, 2H), 3.94 (t, J=5.6 Hz, 1H), 2.21 (t, J=7.4 Hz, 2H), 1.63-48 (m,4H), 1.37-1.27 (m, 2H). LCMS: MS m/z: 449.98 (free base, M+1).

Example 116:4-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)oxy)butanoicacid (Compound 141)

Compound 141 as a TFA salt was synthesized in a manner similar to6-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)oxy)hexanoicacid (Compound 140) in Example 115, replacing tert-butyl6-hydroxyhexanoate with tert-butyl 4-hydroxybutanoate. ¹H NMR (400 MHz,DMSO-d₆) δ 10.87 (br, 3H), 9.09 (br, 1H), 8.84 (br, 1H), 8.14 (s, 1H),7.20 (d, J=4.6 Hz, 1H), 6.91 (d, J=4.6 Hz, 1H), 4.65 (d, J=4.8 Hz, 1H),4.40 (dd, J=11.4, 2.2 Hz, 1H), 4.29-4.20 (m, 2H), 4.10 (t, J=6.5 Hz,2H), 3.94 (dd, J=6.3, 4.9 Hz, 1H), 2.30 (t, J=7.3 Hz, 2H), 1.83 (p,J=6.9 Hz, 2H). LCMS: MS m/z: 421.99 (M+1).

Example 117:5-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)oxy)pentanoicacid (Compound 142)

Compound 142 as a TFA salt was synthesized in a manner similar to6-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)oxy)hexanoicacid (Compound 140) in Example 115, replacing tert-butyl6-hydroxyhexanoate with tert-butyl 5-hydroxypentanoate. ¹H NMR (400 MHz,DMSO-d₆) δ 11.94 (br, 1H), 8.51 (br, 1H), 8.29 (br, 1H), 8.04 (s, 1H),7.07 (d, J=4.6 Hz, 1H), 6.86 (d, J=4.6 Hz, 1H), 6.33 (br, 2H), 4.65 (d,J=4.8 Hz, 1H), 4.41 (d, J=11.1 Hz, 1H), 4.24 (t, J=10.1 Hz, 2H), 4.08(t, J=6.1 Hz, 2H), 3.94 (t, J=5.5 Hz, 1H), 2.25 (t, J=6.9 Hz, 2H),1.65-1.50 (m, 4H). LCMS: MS m/z: 435.99 (M+1).

Example 118:7-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)oxy)heptanoicacid (Compound 143)

Compound 143 as a TFA salt was synthesized in a manner similar to6-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)oxy)hexanoicacid (Compound 140) in Example 115, replacing tert-butyl6-hydroxyhexanoate with tert-butyl 7-hydroxyheptanoate. ¹H NMR (400 MHz,DMSO-d₆) δ 8.62 (br, 1H), 8.38 (br, 1H), 8.05 (s, 1H), 7.08 (d, J=4.5Hz, 1H), 6.86 (d, J=4.6 Hz, 1H), 6.26 (br, 3H), 4.66 (d, J=4.9 Hz, 1H),4.44-4.37 (m, 1H), 4.28-4.18 (m, 2H), 4.06 (t, J=6.6 Hz, 2H), 3.94 (dd,J=6.3, 4.9 Hz, 1H), 2.20 (t, J=7.3 Hz, 2H), 1.62-1.44 (m, 4H), 1.29 (h,J=3.2 Hz, 4H). LCMS: MS m/z: 464.02 (M+1).

Example 119:[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3-[ethoxy(hydroxy)phosphoryl]oxy-4-hydroxy-tetrahydrofuran-2-yl]methylisopropyl carbonate (Compound 144)

A stirred solution of[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methylisopropyl carbonate (Compound 4) (100 mg, 0.265 mmol) and triethylamine(0.2 mL, 1.46 mmol) in MeCN (2.6 mL) at 0° C. was treated with ethyldichlorophosphate (0.04 mL, 0.32 mmol) and was warmed to roomtemperature over 2 hours. The reaction mixture was quenched withsaturated aqueous ammonium chloride (3 mL) and extracted with EtOAc (5mL×3). The combined organic layers were dried over MgSO₄ andconcentrated, and the crude residue was purified by flash columnchromatography using C18 column using acetonitrile and water as eluentsto give Compound 144. ¹H NMR (400 MHz, DMSO-d6) δ 8.06-7.79 (m, 3H),6.95-6.87 (m, 1H), 6.87-6.74 (m, 1H), 4.83-4.68 (m, 2H), 4.45-4.31 (m,2H), 4.25-4.13 (m, 1H), 3.88-3.68 (m, 2H), 1.15-1.03 (m, 3H). LCMS: MS:m/z 486.0 (M+1).

Example 120: isopropyl(2S,3R)-3-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]-2-(dimethylamino)butanoate(Compound 145)

A solution of L-threonine (Intermediate 145a, 5 g, 42 mmol) in MeOH (70mL) was treated with formaldehyde (37 wt % in water, 18.7 mL, 252 mmol)and Pd/C (5 wt % on carbon, 10.7 g, 5.04 mmol). The reaction apparatuswas backfilled with H₂ then the reaction mixture was stirred vigorouslyfor 72 hours. The resulting mixture was filtered over Celite®, and thefiltrate was concentrated to dryness to give desired N-methylatedL-threonine (Intermediate 145b).

A solution of Intermediate 145b (2 g, 13.6 mmol) in DMF (136 mL) wastreated with KOH (762 mg, 13.6 mmol), then reaction mixture was heatedto 80° C. and stirred for 4 hours. The resulting solution was cooled to50° C., then 2-bromopropane (1.4 mL, 14.9 mmol) was added, and thereaction mixture was stirred for 16 hours. The resulting whitesuspension was cooled to room temperature and H₂O (150 mL) was added,and then was extracted with diethyl ether (100 mL×3). The combinedorganic layers were washed with H₂O (100 mL×3), dried over MgSO₄, andconcentrated gently to give N-dimethyl-O-iPr-L-threonine (Intermediate145c). This was used directly in next step without further purification

A solution of 1,1′-carbonyldiimidazole (2.4 g, 14.7 mmol) in DCM (35 mL)was treated with Intermediate 145c (1.86 g, 9.82 mmol), then was left tostir for 16 hours. The resulting solution was washed with H₂O (50 mL×2),and the organic layer was dried over MgSO₄ then concentrated to drynessto give desired carbamate. This was used directly in next step withoutfurther purification.

A solution of Intermediate I (1.5 g, 4.53 mmol) and Intermediate 145d inMeCN (16 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (138mg, 0.905 mmol) then was stirred for 16 hours. The resulting yellowsolution was quenched with saturated aqueous ammonium chloride (20 mL)and extracted with EtOAc (30 mL×3). The combined organic layers weredried over MgSO₄ and concentrated to dryness. The resulting crudeIntermediate 145e was used in next step without further purification,assuming quantitative yield.

A solution of crude Intermediate 145e (2.48 g, 4.53 mmol) in THE (45 mL)was treated with conc. HCl (3.74 mL, 45.3 mmol), then was stirred for 2hours before being quenched with saturated aqueous sodium bicarbonateuntil basic. The mixture was extracted with EtOAc (50 mL×3), and thecombined organic layers were dried over MgSO₄ then concentrated todryness. The resulting crude residue was purified by flash columnchromatography using dichloromethane and methanol as eluents to giveCompound 145. ¹H NMR (400 MHz, DMSO-d6) δ 8.14-7.75 (m, 3H), 6.90 (d,J=4.4 Hz, 1H), 6.78 (d, J=4.5 Hz, 1H), 6.33 (d, J=6.1 Hz, 1H), 5.39 (d,J=5.8 Hz, 1H), 4.97 (dp, J=12.6, 6.5 Hz, 2H), 4.70-4.61 (m, 1H),4.48-4.37 (m, 1H), 4.30-4.16 (m, 2H), 4.02-3.84 (m, 1H), 3.25 (d, J=8.2Hz, 1H), 2.26 (s, 6H), 1.34-1.02 (m, 9H). LCMS: MS m/z: 507.2 (M+1).

Example 121: isopropyl(2S)-4-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]-2-(dimethylamino)butanoate(Compound 146)

Compound 146 was synthesized in a manner similar to isopropyl(2S,3R)-3-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]-2-(dimethylamino)butanoate(Compound 145) in Example 120, replacing L-threonine with L-homoserine.¹H NMR (400 MHz, DMSO-d6) δ 8.05-7.78 (m, 3H), 6.91 (d, J=4.6 Hz, 1H),6.80 (d, J=4.6 Hz, 1H), 6.32 (d, J=6.1 Hz, 1H), 5.42 (d, J=5.8 Hz, 1H),4.94 (p, J=6.3 Hz, 1H), 4.74-4.64 (m, 1H), 4.44-4.33 (m, 1H), 4.27-4.19(m, 2H), 4.12 (t, J=6.5 Hz, 2H), 3.93 (q, J=5.6 Hz, 1H), 3.25-3.19 (m,1H), 2.25 (s, 6H), 1.98-1.84 (m, 2H), 1.25-1.16 (m, 6H). LCMS: MS m/z:507.1 (M+1).

Example 122: neopentylO-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)-N,N-dimethyl-L-threoninate(Compound 147)

Compound 147 was synthesized in a manner similar to isopropyl(2S,3R)-3-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]-2-(dimethylamino)butanoate(Compound 145) in Example 120, replacing 2-bromopropane with1-bromo-2,2-dimethylpropane and purified by HPLC using 10 mM aqueousammonium formate and acetonitrile as eluents. ¹H NMR (500 MHz, DMSO) δ7.97-7.80 (m, 3H), 6.90 (d, J=4.5 Hz, 1H), 6.77 (d, J=4.5 Hz, 1H), 6.33(d, J=6.1 Hz, 1H), 5.38 (d, J=5.9 Hz, 1H), 5.06-4.97 (m, 1H), 4.65 (dd,J=5.8, 5.1 Hz, 1H), 4.44-4.38 (m, 1H), 4.26-4.17 (m, 2H), 3.92 (dd,J=11.1, 5.8 Hz, 1H), 3.76 (q, J=10.5 Hz, 2H), 3.37 (d, J=7.8 Hz, 1H),2.29 (s, 6H), 1.23 (d, J=6.3 Hz, 3H), 0.90 (d, J=13.0 Hz, 9H). LCMS: MSm/z: 535.5 (M+1).

Example 123: (2S,3R)-cyclopentylmethyl3-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2yl)methoxy)carbonyl)oxy)-2-(dimethylamino)butanoate(Compound 148)

Compound 148 was synthesized in a manner similar to isopropyl(2S,3R)-3-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]-2-(dimethylamino)butanoate(Compound 145) in Example 120, replacing 2-bromopropane with(bromomethyl)cyclopentane and purified by HPLC using 10 mM aqueousammonium formate and acetonitrile as eluents. ¹H NMR (500 MHz, DMSO) δ7.92 (s, 3H), 6.89 (d, J=4.5 Hz, 1H), 6.77 (d, J=4.5 Hz, 1H), 6.55-6.40(m, 1H), 5.60-5.45 (m, 1H), 5.03-4.92 (m, 1H), 4.70-4.61 (m, 1H),4.49-4.37 (m, 1H), 4.21 (s, 2H), 3.95 (d, J=7.0 Hz, 2H), 3.93-3.85 (m,1H), 2.54-2.51 (m, 1H), 2.27 (s, 6H), 2.08 (s, 1H), 1.71-1.61 (m, 2H),1.52 (s, 2H), 1.50-1.43 (m, 2H), 1.22 (d, J=6.3 Hz, 3H), 1.20-1.13 (m,2H). LCMS: MS m/z: 547.4 (M+1).

Example 124: cyclopentylO-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)-N,N-dimethyl-L-threoninate(Compound 149)

Compound 149 was synthesized in a manner similar to isopropyl(2S,3R)-3-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]-2-(dimethylamino)butanoate(Compound 145) in Example 120, replacing 2-bromopropane withbromocyclopentane and purifying by HPLC using 10 mM aqueous ammoniumformate and acetonitrile as eluents. ¹H NMR (500 MHz, DMSO) δ 7.99-7.80(m, 3H), 6.89 (d, J=4.5 Hz, 1H), 6.77 (d, J=4.5 Hz, 1H), 6.37 (d, J=6.0Hz, 1H), 5.41 (d, J=6.0 Hz, 1H), 5.12 (s, 1H), 4.98 (dd, J=7.9, 6.4 Hz,1H), 4.65 (dd, J=5.6, 5.2 Hz, 1H), 4.41 (dd, J=14.2, 5.2 Hz, 1H),4.27-4.18 (m, 2H), 3.91 (d, J=5.4 Hz, 1H), 3.27 (d, J=7.9 Hz, 1H), 2.27(s, 6H), 1.85-1.71 (m, 2H), 1.66-1.57 (m, >99.5% 4H), 1.56-1.48 (m 2H),1.20 (d, J=6.4 Hz, 3H). LCMS: MS m/z: 533.4 (M+1).

Example 125: tetrahydro-2H-pyran-4-ylO-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)-N,N-dimethyl-L-threoninate(Compound 150)

Compound 150 was synthesized in a manner similar to isopropyl(2S,3R)-3-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]-2-(dimethylamino)butanoate(Compound 145) in Example 120, replacing 2-bromopropane with4-bromotetrahydropyran and purifying by HPLC using 10 mM aqueousammonium formate and acetonitrile as eluents. ¹H NMR (500 MHz, DMSO) δ7.99-7.82 (m, 3H), 6.90 (d, J=4.4 Hz, 1H), 6.77 (d, J=4.4 Hz, 1H), 6.37(d, J=6.0 Hz, 1H), 5.40 (d, J=5.8 Hz, 1H), 5.06-4.99 (m, 1H), 4.97-4.92(m, 1H), 4.64 (t, J=5.4 Hz, 1H), 4.41 (d, J=9.3 Hz, 1H), 4.28-4.17 (m,2H), 3.91 (d, J=5.2 Hz, 1H), 3.80-3.66 (m, 2H), 3.49-3.37 (m, 2H), 2.29(s, 6H), 1.90-1.74 (m, 2H), 1.59-1.45 (m, 2H), 1.22 (d, J=6.3 Hz, 3H).LCMS: MS m/z: 549.4 (M+1).

Example 126: isopropylO-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)-N,N-dimethyl-L-serinate(Compound 151)

Compound 151 was synthesized in a manner similar to isopropyl(2S,3R)-3-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]-2-(dimethylamino)butanoate(Compound 145) in Example 120, replacing L-threonine with L-serine andpurifying by HPLC using 0.1% v/v trifluoro acetic acid in water andacetonitrile as eluents to afford the corresponding TFA salt. ¹H NMR(500 MHz, DMSO) δ 8.24-8.01 (m, J=61.2 Hz, 2H), 7.96 (s, 1H), 6.96 (d,J=4.6 Hz, 1H), 6.81 (d, J=4.6 Hz, 1H), 6.39 (br. s, 1H), 5.58-5.36 (m,1H), 5.08-4.99 (m, 1H), 4.72-4.63 (m, 3H), 4.59 (br.s, 1H), 4.43 (dd,J=11.7, 2.6 Hz, 1H), 4.34-4.27 (m, 1H), 4.25 (td, J=6.8, 2.5 Hz, 1H),3.92 (dd, J=6.6, 5.0 Hz, 1H), 2.83 (s, J=29.0 Hz, 6H), 1.22 (d, J=6.3Hz, 3H), 1.13 (d, J=6.2 Hz, 3H). LCMS: MS m/z: 493.4 (M+1).

Example 127: cyclopentylmethylO-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)-N,N-dimethyl-L-serinate(Compound 152)

Compound 152 was synthesized in a manner similar to isopropyl(2S,3R)-3-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]-2-(dimethylamino)butanoate(Compound 145) in Example 120, replacing L-threonine with L-serine and2-bromopropane with (bromomethyl)cyclopentane, and purifying by HPLCusing 0.1% v/v trifluoro acetic acid in water and acetonitrile aseluents to afford the corresponding TFA salt. ¹H NMR (500 MHz, DMSO) δ8.21-7.98 (m, 2H), 7.96 (s, 1H), 6.95 (d, J=4.6 Hz, 1H), 6.80 (d, J=4.6Hz, 1H), 6.41 (br. s, 1H), 5.40 (br. s, 1H), 4.72-4.57 (m, 4H), 4.43(dd, J=11.4, 2.1 Hz, 1H), 4.32-4.22 (m, 2H), 4.15-4.08 (m, 1H), 4.03(dd, J=10.6, 7.0 Hz, 1H), 3.91 (dd, J=6.6, 5.0 Hz, 1H), 2.83 (s, J=15.1Hz, 6H), 2.16-2.08 (m, 1H), 1.66-1.57 (m, J=13.0, 8.1 Hz, 2H), 1.53-1.36(m, 4H), 1.21-1.10 (m, 2H). LCMS: MS m/z: 533.5 (M+1).

Example 128: cyclopentylO-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)carbonyl)-N,N-dimethyl-L-serinate(Compound 153)

Compound 153 was synthesized in a manner similar to isopropyl(2S,3R)-3-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxycarbonyloxy]-2-(dimethylamino)butanoate(Compound 145) in Example 120, replacing L-threonine with L-serine and2-bromopropane with bromocyclopentane, and purifying by HPLC using 0.1%v/v trifluoro acetic acid in water and acetonitrile as eluents to affordthe corresponding TFA salt. ¹H NMR (400 MHz, DMSO) δ 8.36-8.04 (m,J=54.1 Hz, 2H), 7.97 (s, 1H), 6.96 (d, J=4.5 Hz, 1H), 6.81 (d, J=4.6 Hz,1H), 6.42 (br. s, 1H), 5.42 (br. s, 1H), 5.26-5.18 (m, 1H), 4.74-4.56(m, 4H), 4.46-4.38 (m, 1H), 4.33-4.21 (m, 2H), 3.91 (dd, J=6.1, 5.2 Hz,1H), 2.84 (s, J=13.1 Hz, 6H), 1.90-1.41 (m, 8H). LCMS: MS m/z: 519.3(M+1).

Example 129:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(4-methoxyphenyl) carbonate (Compound 111)

Compound 111 was synthesized in a manner similar to[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydrofuran-2-yl]methylisopropyl carbonate (Compound 4) in Example 4, replacing isopropylchloroformate with 4-methoxyphenyl carbonochloridate. ¹H NMR (400 MHz,DMSO-d6) δ 7.93 (s, 3H), 7.15-7.08 (m, 2H), 6.97-6.89 (m, 3H), 6.82 (d,J=4.5 Hz, 1H), 6.36 (d, J=6.1 Hz, 1H), 5.46 (d, J=5.7 Hz, 1H), 4.71 (dd,J=6.1, 4.9 Hz, 1H), 4.56-4.46 (m, 1H), 4.38-4.26 (m, 2H), 4.00 (q, J=5.6Hz, 1H), 3.75 (s, 3H). LCMS: MS m/z: 441.93 (M+1)

Example 130:(2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-cyano-5-(((ethoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyldiacetate (Compound 129)

Ethanol (1 equiv) was added to a stirring solution of1,1′-carbonyldiimidazole (1.5 equiv) in DCM (1 M with respect to1,1′-carbonyldiimidazole) at rt, and the reaction mixture was stirredfor 16 h. The reaction mixture was then transferred to a separatoryfunnel, washed with water two times, dried over MgSO₄, and concentratedto afford Intermediate 129a, which was directly used into next stepwithout further purification.

To the solution of Intermediate 129a (1.1 equiv) in MeCN (0.4 M withrespect to Intermediate 129a) was added Intermediate I (1 equiv) at roomtemperature followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 equiv).The resulting solution was stirred at room temperature for 16 h and thenwas quenched with saturated aqueous ammonium chloride. The biphasicmixture was extracted using EtOAc three times, and the combined organiclayers were dried over MgSO₄ and concentrated to afford Intermediate129b, which was directly used in the next step without furtherpurification.

To a solution of Intermediate 129b (1 equiv) in THE (1.2 M with respectto Intermediate 129b) at rt was added conc. HCl (5 equiv) slowly overten minutes. The reaction was then stirred for 6.5 h. The resultingmixture was basified with saturated aqueous sodium bicarbonate andextracted with EtOAc three times, and the combined organic layers weredried over MgSO₄ then concentrated. The crude product was redissolvedinto ethanol, and the total volume was adjusted to approximately 7 mL/g.Slurry formation was observed at rt, and then heptane (7 mL/g) was addedslowly. The slurry was agitated overnight and then the solids werefiltered and rinsed with a mixture of ethanol (1.5 mL/g) and heptane(1.5 mL/g). The solids were dried under vacuum to afford Compound 6 (73%yield). ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (br, 3H), 6.91 (d, J=4.5 Hz,1H), 6.79 (d, J=4.5 Hz, 1H), 6.30 (d, J=6.1 Hz, 1H), 5.40 (d, J=5.8 Hz,1H), 4.69 (dd, J=6.1, 5.0 Hz, 1H), 4.39 (dd, J=10.3, 4.1 Hz, 1H),4.29-4.17 (m, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.94 (q, J=5.8 Hz, 1H), 1.20(t, J=7.1 Hz, 3H). LCMS: MS m/z: 363.9 (M+23).

To a mixture of Compound 6 (1 equiv) and acetic anhydride (2 equiv) inTHE (0.5 M with respect to Compound 6) was added 4-dimethylaminopyridine(0.15 equiv). The mixture was stirred at rt for 1 hr. After thecompletion of the reaction, the reaction mixture was diluted with ethylacetate, washed with water and brine, dried over MgSO₄, andconcentrated. The residue was purified by flash chromatography usingdichloromethane and ethyl acetate as eluants to obtain Compound 129. ¹HNMR (400 MHz, DMSO-d6) δ 7.95 (br, 3H), 6.95 (d, J=4.7 Hz, 1H), 6.81 (d,J=4.6 Hz, 1H), 6.08 (d, J=5.9 Hz, 1H), 5.41 (dd, J=6.0, 4.6 Hz, 1H),4.61 (td, J=4.9, 3.2 Hz, 1H), 4.48 (dd, J=12.2, 3.2 Hz, 1H), 4.33 (dd,J=12.2, 5.1 Hz, 1H), 4.14-4.06 (m, 2H), 2.12 (d, J=1.5 Hz, 6H), 1.19 (t,J=7.1 Hz, 3H). LCMS: MS m/z: 447.99 (M+1).

Example 131: (3S,5S,7S)-adamantan-1-yl(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl)carbonate (Compound 154)

Compound 154 was synthesized in a manner similar to Compound 47(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate) in Example 23, replacing1-methylcyclohexanol with 1-adamantol. 1H NMR (400 MHz, DMSO-d6) δ8.11-7.63 (m, 3H), 6.91 (d, J=4.5 Hz, 1H), 6.79 (d, J=4.5 Hz, 1H), 6.31(d, J=6.1 Hz, 1H), 5.39 (d, J=5.8 Hz, 1H), 4.75-4.60 (m, 1H), 4.35 (dd,J=11.9, 2.9 Hz, 1H), 4.19 (td, J=6.1, 2.9 Hz, 1H), 4.15-4.05 (m, 1H),3.96-3.87 (m, 1H), 2.16-2.09 (m, 4H), 2.03-1.92 (m, 6H), 1.65-1.48 (m,6H).). LCMS: MS m/z: 492.1 (M+23).

Example 132:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(2-(4-methylcyclohex-3-en-1-yl)propan-2-yl) carbonate (Compound 155)

Compound 155 was synthesized in a manner similar to Compound 55((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcycloheptyl) carbonate in Example 32, replacing1-methylcycloheptan-1-ol with 2-(4-methylcyclohex-3-en-1-yl)propan-2-ol.¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.90 (d, J=4.5 Hz, 1H), 6.79(d, J=4.5 Hz, 1H), 6.32 (d, J=6.0 Hz, 1H), 5.39 (d, J=5.8 Hz, 1H),5.36-5.28 (m, 1H), 4.65 (dd, J=6.0, 4.9 Hz, 1H), 4.35 (dd, J=11.8, 2.8Hz, 1H), 4.20 (td, J=6.2, 2.7 Hz, 1H), 4.12 (dd, J=11.8, 5.8 Hz, 1H),3.92 (q, J=5.7 Hz, 1H), 2.02-1.67 (m, 6H), 1.64-1.56 (m, 3H), 1.37 (d,J=11.8 Hz, 6H), 1.28-1.13 (m, 1H). LCMS: MS m/z: 472.1 (M+1).

Example 133:((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl((1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl) carbonate (Compound156)

Compound 156 was synthesized in a manner similar to Compound 47(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methyl(1-methylcyclohexyl) carbonate) in Example 23, replacing1-methylcyclohexanol with tropine and was purified by flashchromatography using dichloromethane, methanol, and triethylamine. 1HNMR (400 MHz, DMSO-d6) δ 7.92 (s, 3H), 6.91 (d, J=4.6 Hz, 1H), 6.82 (d,J=4.5 Hz, 1H), 6.39 (s, 1H), 5.42 (s, 1H), 4.73 (t, J=5.2 Hz, 1H), 4.62(d, J=4.7 Hz, 1H), 4.48-4.34 (m, 1H), 4.29-4.15 (m, 2H), 3.93 (t, J=5.5Hz, 1H), 3.17 (s, 2H), 2.26 (s, 3H), 2.17-2.04 (m, 2H), 1.98 (dd, J=8.1,4.2 Hz, 2H), 1.89-1.80 (m, 2H). LCMS: MS m/z: 459.1 (M+1).

Example A: HEp-2 RSV-Luc5 384-Well Assay

HEp-2 cell line was purchased from ATCC (Manassas, Va. Cat #CCL-23) andmaintained in Dulbecco's Minimum Essential Medium (DMEM) (Corning, N.Y.,N.Y., Cat #15-018CM) supplemented with 10% fetal bovine serum (FBS)(Hyclone, Logan, Utah, Cat #SH30071-03) and 1×Penicillin-Streptomycin-L-Glutamine (Corning, N.Y., N.Y., Cat#30-009-CI). Cells were passaged 2 times per week to maintainsub-confluent densities and were used for experiments at passage 5-20.Respiratory syncytial virus recombinant with luciferase (RSV-Luc5)(≥1×107 TCID50/ml) was purchased from Microbiologics (Saint Cloud,Minn.). Viral replication was determined in HEp-2 cells in the followingmanner.

Compounds are prepared in 100% DMSO in 384-well polypropylene plates(Greiner, Monroe, N.C., Cat #784201) with 8 compounds per plate ingrouped replicates of 4 at 10 serially diluted concentrations (1:3). Theserially diluted compounds were transferred to low dead volume Echoplates (Labcyte, Sunnyvale, Calif., Cat #LP-0200).

The test compounds were spotted to 384-well assay plates (Greiner,Monroe, N.C., Cat #781091) at 200 nL per well. HEp-2 cells wereharvested and suspended in DMEM (supplemented with 10% FBS and 1×Penicillin-Streptomycin-L-Glutamine) and seeded to the pre-spotted assayplates at 4,000 cells per well in 30 μL. RSV-Luc5 viruses were dilutedin DMEM (supplemented with 10% FBS and 1×Penicillin-Streptomycin-L-Glutamine) at 200,000 Infectious Units (IU)per mL and 10 μL per well was added to the assay plates containing cellsand compounds, for an MOI=0.5. The assay plates were incubated for 3days at 37° C. and 5% CO₂. At the end of incubation, One-Glo reagent(Promega, Madison, Wis., Cat #E6120) was prepared. The assay plates andOne-Glo reagent were equilibrated to room temperature for at least 15minutes. 40 μL per well of One-Glo reagent was added and the plates wereincubated at room temp for 15 minutes before reading the luminescencesignal on an EnVision multimode plate reader (Perkin Elmer, Waltham,Mass.). Remdesivir was used as positive control and DMSO was used asnegative control. Values were normalized to the positive and negativecontrols (as 0% and 100% replication, respectively) and data was fittedusing non-linear regression analysis by Gilead's dose response tool. TheEC₅₀ value for each compound was then determined as the concentrationreducing the viral replication by 50%.

Remdesivir

Example B: A549-hACE2 SARS-CoV2-NLuc 384-Well Assay

A549-hACE2 cell line was maintained in Dulbecco's Minimum EssentialMedium (DMEM) (Corning, N.Y., N.Y., Cat #15-018CM) supplemented with 10%fetal bovine serum (FBS) (Hyclone, Logan, Utah, Cat #SH30071-03), 1×Penicillin-Streptomycin-L-Glutamine (Corning, N.Y., N.Y., Cat#30-009-CI) and 10 μg/mL blasticidin (Life Technologies Corporation,Carlsbad, Calif., Cat #A11139-03). Cells were passaged 2 times per weekto maintain sub-confluent densities and were used for experiments atpassage 5-20. SARS Coronavirus 2 recombinant with NanoLuc(SARS-CoV2-NLuc) was obtained from University of Texas Medical Branch(Galveston, Tex.). Viral replication was determined in A549-hACE2 cellsin the following manner.

Compounds are prepared in 100% DMSO in 384-well polypropylene plates(Greiner, Monroe, N.C., Cat #784201) with 8 compounds per plate ingrouped replicates of 4 at 10 serially diluted concentrations (1:3). Theserially diluted compounds were transferred to low dead volume Echoplates (Labcyte, Sunnyvale, Calif., Cat #LP-0200).

The test compounds were spotted to 384-well assay plates (Greiner,Monroe, N.C., Cat #781091) at 200 nL per well using an Echo acousticdispenser (Labcyte, Sunnyvale, Calif.). A549-hACE2 cells were harvestedand suspended in DMEM (supplemented with 2% FBS and 1×Penicillin-Streptomycin-L-Glutamine) and seeded to the pre-spotted assayplates at 10,000 cells per well in 30 μL. SARS-CoV2-NLuc virus wasdiluted in DMEM (supplemented with 2% FBS and 1×Penicillin-Streptomycin-L-Glutamine) at 350,000 Infectious Units (IU)per mL and 10 μL per well was added to the assay plates containing cellsand compounds, for an MOI of 0.35. The assay plates were incubated for 2days at 37° C. and 5% CO₂. At the end of incubation, Nano-Glo reagent(Promega, Madison, Wis., Cat #N1150) was prepared. The assay plates andNano-Glo reagent were equilibrated to room temperature for at least 15minutes. 40 μL per well of Nano-Glo reagent was added and the plateswere incubated at room temperature for 15 minutes before reading theluminescence signal on an EnVision multimode plate reader (Perkin Elmer,Waltham, Mass.). Remdesivir was used as positive control and DMSO wasused as negative control. Values were normalized to the positive andnegative controls (as 0% and 100% replication, respectively) and datawas fitted using non-linear regression analysis by Gilead's doseresponse tool. The EC₅₀ value for each compound was defined as theconcentration reducing the viral replication by 50%.

Example C: NHBE RSV-Luc5 384-Well Assay

Normal Human Bronchial Epithelial (NHBE) cells were purchased from Lonza(Walkersville, Md. Cat #CC2540) and maintained in BEGM BronchialEpithelial Cell Growth Medium BulletKit (Lonza CC-3170).

Cells were thawed, expanded, and were used for experiments at passage 2.Respiratory syncytial virus recombinant with luciferase (RSV-Luc5)(≥1×10⁷ Infectious Units/ml (IU/ml) determined by TCID₅₀) was purchasedfrom Microbiologics (Saint Cloud, Minn.). Viral replication wasdetermined in NHBE cells in the following manner.

Compounds are prepared in 100% DMSO in 384-well polypropylene plates(Greiner, Monroe, N.C., Cat #784201) with 8 compounds per plate ingrouped replicates of 4 at 10 serially diluted concentrations (1:3). Theserially diluted compounds were transferred to low dead volume Echoplates (Labcyte, Sunnyvale, Calif., Cat #LP-0200).

The test compounds were spotted to 384-well assay plates (Greiner,Monroe, N.C., Cat #781091) at 200 nL per well. NHBE cells were harvestedand suspended in BEGM Bronchial Epithelial Cell Growth Medium BulletKitand seeded to the pre-spotted assay plates at 5,000 cells per well in 30μL. RSV-Luc5 virus was diluted in BEGM Bronchial Epithelial Cell GrowthMedium BulletKit at 500,000 Infectious Units (IU) per mL and 10 μL perwell was added to the assay plates containing cells and compounds, foran MOI of 1. The assay plates were incubated for 3 days at 37° C. and 5%CO₂. At the end of incubation, One-Glo reagent (Promega, Madison, Wis.,Cat #E6120) was prepared. The assay plates and One-Glo reagent wereequilibrated to room temperature for at least 15 minutes. 40 μL per wellof One-Glo reagent was added and the plates were incubated at roomtemperature for 15 minutes before reading the luminescence signal on anEnVision multimode plate reader (Perkin Elmer, Waltham, Mass.).Remdesivir was used as positive control and DMSO was used as negativecontrol. Values were normalized to the positive and negative controls(as 0% and 100% replication, respectively) and data was fitted usingnon-linear regression analysis by Gilead's dose response tool. The EC₅₀value for each compound was defined as the concentration reducing theviral replication by 50%.

Example D: CC50 MT4

Cytotoxicity of the compounds was determined in uninfected cells usingthe cell viability reagent in a similar fashion as described before forother cell types (Cihlar et al., Antimicrob Agents Chemother. 2008,52(2):655-65). HEp-2 (1.5×103 cells/well) and MT-4 (2×103 cells/well)cells were plated in 384-well plates and incubated with the appropriatemedium containing 3-fold serially diluted compound ranging from 15 nM to100,000 nM. Cells were cultured for 4-5 days at 37° C. Following theincubation, the cells were allowed to equilibrate to 25° C., and cellviability was determined by adding Cell-Titer Glo viability reagent. Themixture was incubated for 10 min, and the luminescence signal wasquantified using an Envision plate reader. Untreated cell and cellstreated at 2 μM puromycin (Sigma, St. Louis, Mo.) serve as 100% and 0%cell viability control, respectively. The percent of cell viability wascalculated for each tested compound concentration relative to the 00 and1000 controls and the CC₅₀ value was determined by non-linear regressionas a compound concentration reducing the cell viability by 50%.

TABLE D1 RSV RSV SARS- Hep2 NHBE COV2 MT4 Compound EC₅₀ EC₅₀ EC₅₀ CC₅₀Example No. (nM) (nM) (nM) (μM) Example 1 1 422 2184 1871 >46443 Example2 2 6608 9599 >50000 >50000 Example 3 3 545 1597 796 >50000 Example 4 4606 774 2672 >50000 Example 5 5 2903 3550 13227 >50000 Example 6 6 11151008 4416 >50000 Example 7 7 416 1341 915 47440 Example 8 8 301 18381014 >50000 Example 9 9 784 1809 2276 >50000 Example 10 10 3965 299014065 >50000 Example 11 11 4940 2920 20589 >50000 Example 12 12 659 15842349 >50000 Example 13 13 444 1533 1249 39140 Example 14 14 350 3801557 >50000 Example 15 15 530 900 1236 >50000 Example 16 16 1151 9812570 27787 Example 17 17 412 1902 814 >50000 Example 18 18 2872 1212412375 >50000 Example 19 19 1241 5402 7701 >50000 Example 20 20 2019 43548985 >50000 Example 21 21 2383 2253 12903 >50000

TABLE D2 RSV RSV SARS- Hep2 NHBE COV2 MT4 Example Compound EC₅₀ EC₅₀EC₅₀ CC₅₀ No. No. (nM) (nM) (nM) (μM) Example 22 46 2324 11824297 >50000 Example 23 47 2331 1476 3358 >50000 Example 24 48 2348 16714195 25480 Example 25 49 >50000 17653 14251 >50000 Example 26 50 19161371 20444 >50000 Example 27 51 2140 727 7834 38296 Example 28 52 100919 574 38813 Example 29 53 98 833 662 >50000 Example 30 29 109 1305835 >50000 Example 31 54 587 1015 5691 >50000 Example 32 55 13362895 >50000 Example 33 56 1262 1212 2521 >50000 Example 34 57 24512291 >50000 Example 35 58 1359 1067 2241 27077 Example 36 59 786 8114164 >50000 Example 37 60 1582 2685 32945 Example 38 35 650.55 10071907.3 >50000 Example 39 62 >50000 5000 5000 >50000 Example 40 6341618 >50000 >50000 Example 42 64 2656.4 4205.4 >50000 Example 43 651080.1 184.94 3639.6 >50000 Example 44 66 847.01 499.24 3207.5 >50000Example 45 67 1516.4 12832 >50000 Example 46 68 1302.5 3134.8 >50000Example 47 69 1047 987.97 2830.7 >50000 Example 48 70 1721.9 2183.92813.1 >50000 Example 49 71 3014.8 531.5 7821.4 47754 Example 50 72779.49 1823.9 1125.9 >50000 Example 51 73 206.06 1104.6 1899.7 >50000Example 52 74 955.83 2401.3 >50000 Example 53 75 1029.6 321.265061 >50000 Example 54 76 3398.6 >50000 >50000 Example 5577 >50000 >50000 >50000 Example 56 78 3599.4 3579.7 >50000 Example 5779 >50000 >50000 >50000 Example 58 80 2043.8 >50000 >50000 Example 59 81996.33 24444 48302 Example 60 82 2410.6 1550.3 >50000 Example 61 832322.7 24534 20973 Example 62 84 311.46 205.36 1540.3 >50000 Example 6385 165.82 776.15 416.99 >50000 Example 64 86 371.12 1219.1 623.01 >50000Example 65 87 344.61 559.34 1052.8 >50000 Example 66 88 381.87 70.2281627.6 >50000 Example 67 89 664.66 977.86 2689.6 >50000 Example 68 90248.91 180.43 1842.9 >50000 Example 69 91 3641.3 5837.2 14745 >50000Example 70 92 1804.2 3044.8 5630.6 >50000 Example 71 93 11095 1061131711 Example 72 31 321.66 802.6 1083.1 >50000 Example 73 94 1018.6922.57 3630.3 >50000 Example 74 27 144.96 1007.7 657.85 >50000 Example75 96 >50000 >50000 Example 76 97 6158 Example 77 98 8999 Example 78 993153 Example 79 100 >50000 16023 >50000 Example 81 37 4746 3152 >50000Example 80 26 942 844 2389 >50000 Example 82 127 5059.8 13659 >50000Example 83 128 2038.1 7232 >50000 Example 84 129 672.72 5831.3 >50000Example 85 130 2961.7 9042.9 >50000 Example 86 131 4786.5 8260.1 >50000Example 87 132 >50000 >50000 >50000 Example 88 133 >50000 >50000 >50000Example 89 134 1403.6 5134 >50000 Example 90 135 >50000 >50000 >50000Example 91 136 2033 4695.8 >50000 Example 92 106 1396 4560.4 >50000

TABLE D3 EC50 SARS EC50 Com- CoV2 RSVFluc- EC50 CC50 Example poundNanoLuc NHBE 384 RSVFluc- MT4 DM No. No. A549 384 V2 Hep2 384 V2 384logD 93 101 3208.9 1961.1 1844.5 >50000 0.9 94 110 20370 10833 >500001.7 95 40 3691.5 3552.2 >50000 <0.3 96 103 >50000 17666 20673 >50000 3.297 107 >50000 >50000 >50000 >50000 2.5 98 125 1789.8 645.07219.77 >50000 1 1 99 120 1412.7 1255.6 816.34 >50000 1.6 100 121 7965.61556.7 1506 >50000 1.1 101 112 2110.6 453.83 181.13 >50000 1.8 102 1141116.1 965.54 122.66 >50000 1.5 103 115 1756.1 989.53 227.55 >50000 1.4104 116 822.27 864.47 320.84 >50000 2.1 105 117 777.79 1376.3493.91 >50000 2.3 106 118 6803.9 1819.5 1763.4 >50000 0.7 107 119 8824.92193.2 2204.4 >50000 0.9 108 122 707.08 1044.3 289.92 >50000 1.9 109 1231161.1 1805.6 719.86 >50000 2.2 110 137 >50000 9519.7 >50000 >50000 2111 138 21191 >50000 >50000 2 112 139 808.09 1638.9 >50000 2.2 113 1241140.4 624.88 723.04 27580.7 3.7 114 126 1608.8 517.37 27659.6 >5.7 115140 >50000 >50000 >50000 <0.3 116 141 >50000 >50000 >50000 <0.3 117142 >50000 >50000 >50000 <0.3 118 143 35388 >50000 >50000 <0.3 119144 >50000 3056.6 >50000 0.4 120 145 3484.7 3148.8 >50000 1.85 121 1467678.9 8252.4 >50000 1.5 122 147 2849.4 2467.2 >50000 2.5 123 148 2050.92104.7 >50000 2.7 124 149 2420.7 2548 >50000 2.2 125 150 2368.93075.3 >50000 1.3 126 151 2756.1 2892.3 >50000 1.3 127 152 1280.53633.4 >50000 2.2 128 153 2673.9 3237.3 >50000 1.7 129 111 3424.1 1298220.04 >50000 1.5 131 154 33999 10998 11717 >50000 2.6 133 156 3144249847 >50000 0.3 132 155 3186.1 1123.3 1566.7 >50000 2.8

Example E: Rat Pharmacokinetics Assay

Ester Reference Compound, Compounds 1 to 4, Compound 6, and Compound 10were dosed orally by gavage to male Sprague-Dawley rats (n=3/group);Ester Reference Compound at 6 mg/kg in 2.5% Dimethyl sulfoxide; 10%Kolliphor HS-15; 10% Labrasol; 2.5% Propylene glycol and 75% water, pH2.5; Compound 1 at 6.7 mg/kg and Compound 3 at 7.0 mg/kg in 2.5%Dimethyl sulfoxide; 10% Kolliphor HS-15; 10% Labrasol; 2.5% Propyleneglycol and 75% water, pH 5.9; Compound 2 at 8.4 mg/kg in 10% Dimethylsulfoxide; 40% Kolliphor HS-15; 40% Labrasol and 10% Propylene glycoland 3^(rd) Ester Reference Compound at 6.7 mg/kg, Compound 4 at 6.5mg/kg, Compound 6 at 6.2 mg/kg, Compound 10 at 6.8 mg/kg and Compound128 and Compound 129 at 75 mg/kg in 2.5% Dimethyl sulfoxide; 10%Kolliphor HS-15; 10% Labrasol; 2.5% Propylene glycol and 75% water, pH5.8. Blood samples were collected into pre-chilled collection tubescontaining K₂EDTA and processed to plasma at 10 time points over a spanof pre-dose to 24 h post-administration. Plasma samples were subject toprotein precipitation with a 12.5-fold volume of methanol, vortexed andcentrifuged. Supernatants were transferred and evaporated to drynessunder nitrogen and reconstituted with 5% acetonitrile in water.Separation was achieved on a Phenomenex Synergi Polar-RP column, amobile phase A of 10 mM ammonium formate with 0.1% formic acid in waterand a mobile phase B of 0.1% formic acid in acetonitrile with astep-wise linear gradient from 5 to 95% mobile phase B. An LCMS/MSmethod was used to measure the concentrations of the Reference CompoundA and either Ester Reference Compound, 3^(rd) Ester Reference Compound,Compounds 1-4, Compound 6, Compound 10, Compound 128 or Compound 129 inplasma. Data for Reference Compound A following oral administration ofeither Ester Reference Compound, 3^(rd) Ester Reference Compound,Compounds 1 to 4, Compound 6, Compound 10, Compound 128 or Compound 129is tabulated below.

TABLE E1 Oral Dose Reference Reference (mg-eq Compound CompoundReference Oral Reference A A Compound Dose Compound C_(max) AUC_(inf.) ACompound No. mg/kg A)/kg (nM) (nM · h) F %ª Ester Reference 6 4.8 21007570 63.6 Compound 3^(rd) Ester 6.7 5 4910 12000 101 Reference Compound 1 6.7 5 2760 9720 77.1  2 8.4 5 2000 8620 68.4  3 7.0 5 5330 12200 96.6 4 6.5 5 5470 10200 81.0  6 6.2 5 2130 7630 60.6  10 6.8 5 1790 632050.1 128 75 50.4 37600 136000 107 129 75 48.8 29300 132000 107 ^(a)basedon reference compound A mg-eq/kg dose; using IV data from 1 mg/kg doseof reference compound A

Example F: Monkey Pharmacokinetics Assay

Ester Reference Compound, Compounds 1 to 4, Compound 6, and Compound 10were dosed orally by gavage to male rhesus monkeys (n=3/group); EsterReference Compound at 12.4 mg/kg in 2.5% DMSO; 10% Kolliphor HS-15; 10%Labrasol; 2.5% Propylene glycol and 75% water, pH 2.2; Compound 1 at13.4 mg/kg and Compound 3 at 13.9 mg/kg in 2.5% DMSO; 10% KolliphorHS-15; 10% Labrasol; 2.5% Propylene glycol and 75% water; Compound 2 at16.9 mg/kg in 10% Dimethyl sulfoxide; 40% Kolliphor HS-15; 40% Labrasoland 10% Propylene glycol and Compound 4 at 13.0 mg/kg, Compound 6 at12.5 mg/kg and Compound 10 at 13.5 mg/kg in 2.5% Dimethyl sulfoxide; 10%Kolliphor HS-15; 10% Labrasol; 2.5% Propylene glycol and 75% water, pH5.8. Blood samples were collected into pre-chilled collection tubescontaining K₂EDTA with dichlorvos (2 mM final concentration with bloodadded) and processed to plasma at 10 timepoints over a span of pre-doseto 24 h post-administration. Plasma samples were subject to proteinprecipitation with a 12.5-fold volume of methanol, vortexed andcentrifuged. Supernatants were transferred and evaporated to drynessunder nitrogen and reconstituted with 5% acetonitrile in water.Separation was achieved on a Phenomenex Synergi Polar-RP column, amobile phase A of 10 mM ammonium formate with 0.1% formic acid in waterand a mobile phase B of 0.1% formic acid in acetonitrile with astep-wise linear gradient from 5 to 95% mobile phase B. An LC-MS/MSmethod was used to measure the concentrations of the Reference CompoundA and either Ester Reference Compound, Compounds 1 to 4, Compound 6, orCompound 10 in plasma. Data for Reference Compound A following oraladministration of either Ester Reference Compound, Compounds 1 to 4,Compound 6, or Compound 10 is tabulated below.

TABLE F1 Reference Oral Oral Dose Reference Compound A Reference Dose(mg-eq Reference Compound A AUC_(inf.) Compound A Compound No: mg/kgCompound A)/kg C_(max) (nM) (nM · h) F %^(a) Ester Reference 12.4 104100 11300 18.9 Compound 1 13.4 10 5770 21900 36.4 2 16.9 10 1600 1250020.8 3 13.9 10 10500 26400 43.9 4 13.0 10 6650 25700 42.8 6 12.5 10 779027300 45.6 10 13.5 10 3300 11600 19.3 ^(a)based on reference compound Amg-eq/kg dose; using IV data from 1 mg/kg dose of reference compoundA.PK for Compound 4, Compound 48, Compound 97, Compound 128, Compound129, Compound 145, Ester Reference Compound, 2^(nd) Ester ReferenceCompound, and 3^(rd) Ester Reference Compound was determined incynomolgus monkeys by analogus procedure described above for rhesusmonkeys. Reference Oral Dose Reference Compound A Reference Example(mg-eq Reference Compound A AUC_(inf.) Compound A Compound No: No.Compound A)/kg C_(max) (nM) (nM · h) F %^(a) 4 4 25.5 14900 74800 47 4824 31.3 8270 44100 23 145 120 31.8 6510 25200 13 97 76 28.2 10900 4450025 128 83 26.5 20500 78900 48 129 84 25.2 32200 90200 58 Reference —9.43 7570 21800 37 Ester Compound 2^(nd) Reference — 11.6 7830 34300 48Ester Compound 3^(rd) Reference — 11.6 10500 37900 53 Ester Compound

Example G: GI S9 Stability

Duplicate aliquots of test compound or positive control substrate(GS-7340) were added to S9 stock diluted with 100 mM phosphate bufferedsaline, pH 7.4, to obtain a protein concentration of 1.0 mg/mL. The S9metabolic reactions were initiated by the addition of the substrates tothe S9 reaction mixture to a final concentration of 2 μM. At 0, 10, 20,30, 60 and 120 min, 25 mL aliquots of the reaction mixture weretransferred to plates containing 225 ml of IS/Q solution. Afterquenching, the plates were centrifuged at 3000′ g for 30 minutes, and150 μL aliquots of each supernatant were diluted with 150 μL water.Aliquots (10 mL) of the diluted supernatant were analyzed on a ThermoQ-Exactive mass spectrometer as described below.

GI S9 Stability—No phenylmethylsulfonyl fluoride (PMSF): Similar to theprocedure described above, test compounds were incubated at 2 μM with 1mg/mL PMSF-free Intestinal S9 fractions. Samples are removed at 6 timepoints over the course of a 120 min experiment and the parent compounddisappearance and reference compound A formation is determined by massspectrometry.

G1 stability data for select compounds is presented in Table K1 belowand in FIG. 1 .

Example H: Plasma Stability

Duplicate aliquots of plasma were warmed to 37° C. and the metabolicreactions initiated by the addition of test compound (6 mL of 0.1 mMDMSO stock) or plasma stability standard (GS-7340) to obtain a finalsubstrate concentration of 2 μM. At 0.05, 0.5, 1, 2, 3 and 4 hr, 25 mLaliquots of the reaction mixture were transferred to plates containing225 ml of IS/Q quenching solution. After quenching, the plates werecentrifuged at 3000′ g for 30 minutes, and 150 μL supernatant wasdiluted with 150 μL water. Aliquots (10 mL) of the diluted supernatantwere analyzed on a Thermo Q-Exactive mass spectrometer as describedbelow.

Example I: CES1/2 Stability

Test compounds or positive control substrates (oseltamivir for CES1enzymes or procaine for CES2) were incubated with individual Supersomepreparations (final CES concentration 1.5 mg/ml) in 0.1 M potassiumphosphate buffer (pH 7.4) at 37° C. Substrates were added to a finalconcentration of 2 μM to initiate the reaction. The final incubationvolume was 250 mL. Aliquots were removed after incubation for 0, 10, 30,60 and 120 min. The reactions were stopped by the addition of IS/Q.Following protein precipitation and centrifugation, 150 mL ofsupernatant was diluted with an equal volume of water prior to LC-MSanalysis. For procaine 150 mL of supernatant was dried down andreconstituted with 250 mL water. All samples were analyzed by LC-MS andthe PAR values were used for quantification.

Example J: Hepatic S9 Stability

Duplicate aliquots of test compound or positive control substrate(GS-7340) were added to S9 stock diluted with 100 mM potassium phosphatebuffer, pH 7.4, to obtain a protein concentration of 2.4 mg/mL. The S9metabolic reactions were initiated by the addition of the substrates tothe S9 reaction mixture to a final concentration of 2 μM. At 2, 12, 25,45, 65 and 90 min, 25 mL aliquots of the reaction mixture weretransferred to plates containing 225 ml of IS/Q solution. Afterquenching, the plates were centrifuged at 3000′ g for 30 minutes, and150 μL aliquots of each supernatant were diluted with 150 μL water.Aliquots (10 mL) of the diluted supernatant were analyzed on a ThermoQ-Exactive mass spectrometer as described below.

Example K: Liquid Chromatography/Mass Spectroscopy Methods for S9 andPlasma Stability

Quantification of test compounds, Reference Compound A (S9 stabilityassay nucleoside metabolite), and controls was performed byanalyte/internal standard peak area ratio (PAR) values measured on aThermo Q-Exactive mass spectrometer coupled to a Dionex UltiMate 3000HPLC with a Leap Technologies HTC PAL autosampler. The column used foranalysis of test compounds and Reference Compound A was a Waters AcquityBEH C18 (1.7 mm particle size, 2.1′ 50 mm). The column used for control(GS-7340) was a Thermo Hypersil GOLD (1.9 mm particle size, 2.1′ 50 mm).Mobile phase A consisted of 0.100 (v/v) formic acid in water. Mobilephase B consisted of 0.10% (v/v) formic acid in acetonitrile. Elution ofanalytes was achieved by a series of linear gradients of acetonitrile inwater containing 0.10% (v/v) formic acid. The mass spectrometer wascalibrated on a weekly basis and mass tolerance of 5 ppm was used.

TABLE K1 Example Compound GIS9 Human GIS9-HUMAN-NoPMSF STA Human No. No.T1/2 T1/2 Plasma 37 1 1 112.79 1.45 28.434 2 2 156.56 344.3 3 3 81.0450.8 82.745 4 4 252.67 0.903 107.92 5 5 789 74.831 1388.9 6 6 712.674.085 55.852 7 7 53.99 6.563 8 8 159.49 0.58 11.698 9 9 311.41 156.68 1010 789 43.569 11 11 789 135.19 12 12 57.974 35.623 13 13 35.305 3 14 1456.255 1.067 262.42 15 15 33.113 40.503 16 16 1.007 30.6 17 17 18 18 1919 27.405 1584 20 20 21 21 22 46 439.12 144.53 553.13 23 47 151.4 158424 48 10.1 1584 25 49 521.7 1584 26 50 15.231 430.4 27 51 10.969 1366.828 52 0.655 85 29 53 0.636 13 30 29 0.617 139 31 54 692.28 4.325 108 3255 0.596 75.665 33 56 16.5 77.644 34 57 317.5 35 58 1.191 1584 36 591.435 0.869 84.318 37 60 44.853 1584 38 35 0.593 139.6 39 62 31.066488.7 40 63 181.47 1584 42 64 0.993 3 43 65 0.621 14.9 44 66 0.491 24.245 67 10.467 1177.1 46 68 46.06 266.43 47 69 48.7 294.49 48 70 72.9721399.3 49 71 25.8 1584 50 72 0.623 31.1 51 73 0.588 70 52 74 30.32205.11 53 75 0.884 277.1 54 76 38.86 1584 55 77 792 383.67 56 78 72.07336.23 57 79 0.681 17.837 58 80 0.847 604.23 59 81 0.688 195.87 60 82 2193.22 61 83 12.1 1584 62 84 0.955 327.2 63 85 0.621 38.6 64 86 0.68448.6 65 87 1.248 28.7 66 88 4.912 1584 67 89 0.59 188.5 68 90 0.591169.9 69 91 41.971 285 70 92 237.8 139.9 71 93 1.017 28.444 72 31 0.85732.4 73 94 1.13 105.4 74 113 0.605 35.4 75 96 789 1584 76 97 3.645 6.66977 98 789 884.09 78 99 96.647 173.49 79 100 80 26 0.487 33.7 81 37 0.58953 82 127 0.957 12.071 83 128 0.59 9.735 84 129 0.623 3 85 130 1.586409.28 86 131 2.64 150.92 87 132 0.624 12.304 88 133 0.623 73.357 89 13465.405 90 135 0.653 96.462 91 136 1.013 463.08 92 106 0.66 30.917 98 1250.582 12.2 99 120 0.605 38.7 100 121 1.583 107.7 101 112 1.774 28.8 102114 1.212 26.8 103 115 0.581 41.2 104 116 0.63 26.4 105 117 0.616 86 106118 4.115 59.4 107 119 2.982 40.7 108 122 0.637 34.1 109 123 0.615 96.5110 137 8.055 676.3 112 139 1.368 150.07 113 124 0.744 192.3 114 12697.584 79.1 115 140 783.41 1322.1 116 141 789 902.37 117 142 789 1584118 143 789 800.58 120 145 32.763 299.49 121 146 174.12 497.93 129 11153.11 3.928 35 131 154 278.9 1584 133 156 789 248.79 132 155 77.5 1584

Example L: CACO-2 Permeability

Pre-plated Caco-2 cells (clone C2BBel) were obtained from Sigma-Aldrich,Inc. (Atlanta, Ga.). Cell monolayers were grown to confluence oncollagen-coated, microporous, polycarbonate membranes in 24-welltranswell plates for 21 days. The permeability assay buffer in donorwells was Hanks' balanced salt solution (HBSS) containing 10 mM HEPESand 15 mM glucose at a pH of 6.5 containing 200 μM BNPP. The receiverwells used HBSS buffer containing 10 mM HEPES and 15 mM glucose at a pHof 7.4 and supplemented with 1% BSA. After an initial equilibration withtransport buffer, TEER values were read to test membrane integrity. Theexperiment was started by the addition of buffers containing testcompounds, 200 μl and 1000 μl in the apical and basolateral chamber,respectively. At 0- and 2-hour post dose, 10 μL was sampled from donorcompartment and was immediately diluted in 190 μL of 20% methanol. At 1and 2 hours post dose, 100 μl of solution was taken from the receivercompartments and was immediately diluted in 100 μl of 20% methanol.Removed buffer was replaced with fresh buffer and a correction wasapplied to all calculations for the removed material. Each compound wastested in 2 separate replicate wells for each condition. All sampleswere then extracted with 400 μl 100% acetonitrile with internal standardto precipitate protein. Cells were dosed on the apical or basolateralside to determine forward (A to B) and reverse (B to A) permeability. Totest for non-specific binding and compound instability, the total amountof drug was quantitated at the end of the experiment and compared to thematerial present in the original dosing solution as a percent recovery.Formation of the parent compound (GS-441524; Reference Compound A) wasmonitored in assay wells dosed with the prodrug. Samples were analyzedby LC-MS/MS.

TABLE L1 Example No Compound No. DM Caco2 A to B DM Caco2 B to A 1 10.275 3.853 2 2 1.17 8.69 3 3 1.23 9.8 4 4 0.545 5.29 5 5 6 6 0.21 2.777 7 0.52 8.98 8 8 9 9 0.39 5.17 10 10 0.08 1.39 11 11 12 12 1.15 13.7313 13 0.59 8.8 14 14 1.84 21.7 15 15 1.46 12 16 16 17 17 18 18 19 19 2020 21 21 1.36 8.33 22 46 0.76 10.66 23 47 1.68 11.38 24 48 6.19 12.52 2549 0.13 3.48 26 50 0.13 2.76 27 51 4.35 17.19 28 52 6.95 13.04 29 532.34 10.58 30 29 1.91 12.29 31 54 0.25 3.8 32 55 0.38 1.89 33 56 0.351.83 34 57 35 58 5.67 6.86 36 59 11.61 17.7 37 60 0.12 0.32 38 35 0.9510.64 39 62 4.19 12.12 40 63 1.18 12.46 42 64 0.39 4.6 43 65 3.07 7.2344 66 45 67 0.99 9.76 46 68 0.98 7.09 47 69 1 4.74 48 70 0.88 6.91 49 714.02 13.65 50 72 2.52 10.69 51 73 0.48 4.69 52 74 3.25 9.88 53 75 54 762.13 12.17 55 77 0.27 5.58 56 78 0.2 4.2 57 79 0.61 9.26 58 80 1.35 0.9559 81 7.77 14.74 60 82 2.73 20.67 61 83 5.3 25.42 62 84 0.27 6.99 63 8564 86 65 87 1.79 10.98 66 88 2.72 12.82 67 89 68 90 0.9 7.41 69 91 0.020.5 70 92 0.07 0.48 71 93 1.2 8.3 72 31 0.68 13 73 94 0.13 2.19 74 1135.21 13.91 75 96 0.09 4.05 76 97 0.04 2.15 77 98 0.02 5.65 78 99 0.112.47 79 100 11.73 22.71 80 26 0.07 0.36 81 37 0.5 7.54 82 127 83 1283.35 5.69 84 129 3.505 6.635 85 130 0.12 2.54 86 131 2.01 15.52 87 13212.34 13.86 88 133 17.25 16.82 89 134 90 135 3.87 18.05 91 136 4.33 5.792 106 4.975 9.5 99 120 0.77 8.35 100 121 0.08 4.15 101 112 2.53 15.81102 114 2.07 11.26 103 115 0.91 8.32 104 116 4.18 17.53 105 117 6.1810.53 106 118 0.07 1.67 107 119 0.07 1.91 109 123 3.18 9.88 110 137 0.9811.37 112 139 0.99 12.98 113 124 0.08 7.35 114 126 0.01 0.03 115 1400.04 0.12 116 141 0.05 0.08 117 142 0.02 0.07 120 145 0.2 8.475 121 1460.06 7.15 129 111 0.625 11.22 131 154 2.08 14.67 133 156 0.12 0.13 132155 3.06 10.35 Reference Ester Compound 0.12 0.62 2^(nd) Reference EsterCompound 11.97 6.74 3^(rd) Reference Ester Compound 5.07 8.91 ReferenceCompound A 0.12 1.52

Example M: Thermodynamic Solubility in pH17 Buffered Solution

The aqueous solubility of compounds over a time of 24 hours wasassessed. Solubility was determined at ambient temperature in a 50 mMphosphate buffered pH7 solution with 150 mM NaCl (to achieveisotonicity). Solids were added to the buffered solution in 1.5-mLEppendorf tubes, vortexed for 1 minute, then agitated for 24 hours in anEppendorf ThermoMixer C. To determine concentration in solution, thesuspensions were centrifuged for 15 min at 15,000 rpm. Supernatants werediluted to a volume of 1 mL with 30:70 v/v acetonitrile:water. Alldiluted supernatants were analyzed by UPLC using a Waters Acquity UPLCwith a PDA UV detector.

TABLE M1 Solubility of Exemplary and Reference Compounds Example No.Compound No. Sol pH 7 4 4 1.85 6 6 3.02 13 13 0.12 14 14 0.21 15 15 0.2621 21 — 36 59 0.01 39 62 0.1 22 46 0.45 53 75 — 27 51 0.08 110 137 0.1344 66 — 35 58 0.02 43 65 0.045 23 47 0.1 25 49 2.03 24 48 0.19 37 60 —40 63 0.82 59 81 0.06 57 79 0.26 45 67 — 56 78 0.89 54 76 0.37 55 774.64 120 145 2.35 71 93 0.62 75 96 1.25 76 97 6.02 88 133 0.24 83 1281.42 84 129 0.72 92 106 0.08 N/A Ester Reference Compound 0.96 N/A2^(nd) Ester Reference Compound 0.01 N/A 3^(rd) Ester Reference Compound1.38

Example N: Stability in pH12 and pH17 Buffered Solutions

The aqueous stability of compounds over a time of 24 hours at 40° C. wasassessed. Stability was determined in 50 mM phosphate buffered solutionsat both pH2 and pH7, with 150 mM NaCl (to achieve isotonicity). 3-5 mgof solid compounds were added to 7 mL scintillation vials. Acetonitrilewas added to each vial to produce a 1 mg/mL stock solution. Stocksolutions were diluted to 50 μg/mL in either pH2 or pH7 phosphatebuffer, to a volume of 1 mL. For each compound and pH condition, 50μg/mL samples were prepped in duplicate. One sample was placed on theUPLC tray at 40° C. for analysis, and the second sample was placed in a40° C. oven for storage. Sample preps for each compound were offset by40 minutes to account for run time on UPLC.

Samples in the UPLC tray were analyzed by UPLC using a Waters AcquityUPLC with a PDA UV detector. Concentration timepoints were measured at0, 3, 6, 9, and 12 hrs. After 24 hrs, samples in the 40° C. oven wereremoved and analyzed by UPLC.

The results for exemplary compounds are summarized in the Tables N1 andN2 below and also presented in FIG. 2 . In FIG. 2 , % AN stands for %area normalized. That is, % AN is the area of the compound peak relativeto the sum of areas of all the peaks in the UPLC chromatogram. Forexample, if there were two peaks, compound peak with an area of 9 andanother peak with an area of 1, then the % AN of the compound peak wouldbe 90%.

TABLE N1 Stability of exemplary and reference compounds at pH2. CompoundCompound Compound 129 of 128 of 3^(rd) Ester 59 of 2^(nd) Ester CompoundEster Example Example Reference Example Reference 4 of Reference 84 83Compound 36 Compound Example 4 Compound 0 hr 100.0 100.0 100.0 100.0100.0 98.5 98.5 3 hr 98.4 98.3 96.3 100.0 100.0 98.3 97.8 6 hr 96.9 96.793.8 100.0 100.0 98.5 97.3 9 hr 95.5 95.2 91.5 100.0 98.3 98.4 96.7 12hr 94.0 93.8 88.7 98.9 97.7 98.5 96.1 24 hr 89.4 89.3 82.1 97.9 96.298.3 94.4 All values listed are % AN values.

TABLE N2 Stabiliy of exemplary and reference compounds as pH2 and pH7.pH2 Stability pH7 Stability Compound No. 24 h % AN 24 h % AN 3^(rd)Ester Reference Compound 82 79 4 98 97 6 100 100 13 98 97 14 97 97 15 9897 21 0 92 46 4 8 47 1 3 48 100 99 49 97 94 51 98 97 58 2 7 59 98 93 600 0 62 61 10 63 3 0 65 90 80 66 2 0 67 95 91 75 0 — 76 92 91 77 98 95 7890 0 79 88 77 81 100 98 93 94 75 96 96 95 97 98 85 106 100 91 128 89 78129 89 78 133 95 98 137 80 97 145 93 0

Example O: Monkey Pharmacokinetics Assay (Solid/Suspension)

Ester Reference Compound, Compound 4, Compound 128 and Compound 129 weredosed orally as tablets to male and/or female cynomolgus monkeys(n=3/group) at 100 mg-eq fixed in 4% crospovidone; 1% magnesium stearateand 45% cellulose; 3^(rd) Ester Reference Compound by oral gavage as asuspension at 100 mg-eq fixed in 1% poloxamer 188; 99% water; Compounds13-15, Compound 46, Compounds 48-49, Compounds 58-59, Compounds 62-63,Compound 76, Compound 79, Compound 93 and Compound 106 at 100 mg-eqfixed and Compound 65 at 20 mg-eq fixed by oral gavage as a suspensionin 0.5% methylcellulose 0.1% polysorbate 80; 99.4% water. Blood sampleswere collected into pre-chilled collection tubes containing K₂EDTA withdichlorvos (2 mM final concentration with blood added) and processed toplasma at 10 timepoints over a span of pre-dose to 24 hpost-administration. Plasma samples were subject to proteinprecipitation with a 12.5-fold volume of methanol, vortexed andcentrifuged. Supernatants were transferred and evaporated to drynessunder nitrogen and reconstituted with 5% acetonitrile in water.Separation was achieved on a Phenomenex Synergi Polar-RP column, amobile phase A of 10 mM ammonium formate with 0.1% formic acid in waterand a mobile phase B of 0.1% formic acid in acetonitrile with astep-wise linear gradient from 5 to 9500 mobile phase B. An LC-MS/MSmethod was used to measure the concentrations of the Reference CompoundA and either Ester Reference Compound, 3^(rd) Ester Reference Compound,Compound 4, Compounds 13-15, Compound 46, Compounds 48-49, Compounds58-59, Compounds 62-63, Compound 65, Compound 76, Compound 79, Compound93, Compound 106, Compound 128 or Compound 129 in plasma. Data forReference Compound A following oral administration of either EsterReference Compound, 3^(rd) Ester Reference Compound, Compound 4,Compounds 13-15, Compound 46, Compounds 48-49, Compounds 58-59,Compounds 62-63, Compound 65, Compound 76, Compound 79, Compound 93,Compound 106, Compound 128 or Compound 129 is tabulated below.

TABLE O1 PK Data for Exemplary and Reference Compounds Oral DoseReference (mg-eq Reference Compound Reference Reference Compound ACompound Compound Oral Dose Compound A AUC_(inf.) A No: mg/kg A) C_(max)(nM) (nM · h) F %ª Ester 29 100 5540 27100 18 Reference Compound 3rdEster 33 100 15800 45000 32 Reference Compound 4 32 100 10600 29500 1914 40 100 8640 50000 27 65 8 20 4490 12500 37 128 38 100 13600 65500 41129 46 100 27400 87400 51 ^(a)based on reference compound A mg-eq/kgdose; using IV data from 1 mg/kg dose of reference compound A.

TABLE O2 F % for Additional Exemplary Compounds Compound No. Cyno F %suspension (unless noted) 13 10 15 18 46 30 48 12 49 6 58 6 59 5 62 1863 12 76 34 79 8 93 47 106 13

All references, including publications, patents, and patent documentsare incorporated by reference herein, as though individuallyincorporated by reference. The present disclosure provides reference tovarious embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the present disclosure. The descriptionis made with the understanding that it is to be considered anexemplification of the claimed subject matter and is not intended tolimit the appended claims to the specific embodiments illustrated.

1-166. (canceled)
 167. A compound of Formula:

or a pharmaceutically acceptable salt thereof. 168-171. (canceled) 172.A pharmaceutical composition comprising the compound of claim 167, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.
 173. (canceled)
 174. Thepharmaceutical composition of claim 172, wherein the pharmaceuticalformulation is for oral administration.
 175. A method of treating acoronavirus infection in a human in need thereof, wherein the methodcomprises administering to the human the compound of claim 167, or apharmaceutically acceptable salt thereof.
 176. The method of claim 175,wherein the compound, or a pharmaceutically acceptable salt thereof, isadministered to the human via oral administration.
 177. The method ofclaim 175, wherein the method comprises administering to the human atleast one additional therapeutic or prophylactic agent. 178.-179.(canceled)
 180. The method of claim 175, wherein the coronavirusinfection is a zoonotic coronavirus infection. 181-185. (canceled) 186.The method of claim 175, wherein the coronavirus infection is aSARS-CoV-2 infection. 187-212. (canceled)
 213. A compound of Formula:


214. A pharmaceutical composition comprising the compound of claim 213and one or more pharmaceutically acceptable excipients.
 215. Thepharmaceutical composition of claim 214, wherein the pharmaceuticalformulation is for oral administration.
 216. A method of treating acoronavirus infection in a human in need thereof, wherein the methodcomprises administering to the human the compound of claim
 213. 217. Themethod of claim 216, wherein the compound is administered to the humanvia oral administration.
 218. The method of claim 216, wherein themethod comprises administering to the human at least one additionaltherapeutic or prophylactic agent.
 219. The method of claim 216, whereinthe coronavirus infection is a zoonotic coronavirus infection.
 220. Themethod of claim 216, wherein the coronavirus infection is a SARS-CoV-2infection.